GAB2

Gene Summary

Gene:GAB2; GRB2-associated binding protein 2
Location:11q14.1
Summary:This gene is a member of the GRB2-associated binding protein (GAB) gene family. These proteins contain pleckstrin homology (PH) domain, and bind SHP2 tyrosine phosphatase and GRB2 adapter protein. They act as adapters for transmitting various signals in response to stimuli through cytokine and growth factor receptors, and T- and B-cell antigen receptors. The protein encoded by this gene is the principal activator of phosphatidylinositol-3 kinase in response to activation of the high affinity IgE receptor. Two alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:GRB2-associated-binding protein 2
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Signal Transducing Adaptor Proteins
  • siRNA
  • Genomics
  • Chronic Myelogenous Leukemia
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • GRB2 Adaptor Protein
  • Cell Proliferation
  • Hematopoietic Stem Cells
  • Breast Cancer
  • fms-Like Tyrosine Kinase 3
  • Cell Movement
  • Enzyme Activation
  • Protein Kinase Inhibitors
  • Tyrosine
  • Phosphorylation
  • Chromosome 11
  • Intracellular Signaling Peptides and Proteins
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
  • Oligonucleotide Array Sequence Analysis
  • Gene Amplification
  • Apoptosis
  • Signal Transduction
  • Mutation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Estrogen Receptors
  • Single Nucleotide Polymorphism
  • Drug Resistance
  • Phosphoproteins
  • TOR Serine-Threonine Kinases
  • Western Blotting
  • Gene Expression
  • Acute Myeloid Leukaemia
  • STAT5 Transcription Factor
  • FISH
  • Pyrimidines
  • Fusion Proteins, bcr-abl
  • src Homology Domains
  • Ovarian Cancer
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GAB2 (cancer-related)

Bozok Cetintas V, Tezcanli Kaymaz B, Aktug H, et al.
Capsaicin induced apoptosis and gene expression dysregulation of human acute lymphoblastic leukemia CCRF-CEM cells.
J BUON. 2014 Jan-Mar; 19(1):183-90 [PubMed] Related Publications
PURPOSE: Capsaicin, an ingredient of red chili pepper, has possible tumorigenicity/genotoxicity properties. We aimed to determine the effects of capsaicin on the proliferation and gene expression profiles of acute lymphoblastic leukemia (ALL) CCRF-CEM cell line.
METHODS: Cell viability and IC50 dose was determined by WST cytotoxicity assay. qRT-PCR, immunohistochemical staining and western blot methods were used to determine target genes' expression levels. Apoptosis was evaluated by measuring the caspase-3 activity.
RESULTS: Capsaicin inhibited the proliferation of CCRFCEM cells in a dose-dependent manner. Increased mRNA expressions of caspase gene family members, activated caspase-3 and decreased mRNA and protein expression of BCL-2 gene indicated apoptotic response to capsaicin. Moreover capsaicin treatment suppressed significantly the expression of the key cell signaling pathways of KRAS, AKT, GAB2, PTPN11, BRAF, INPP5D, MAPK7.
CONCLUSION: Capsaicin induces apoptosis in CCRF-CEM cells and this response is associated with downregulation of cell signaling pathways.

Dunn GP, Cheung HW, Agarwalla PK, et al.
In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene.
Proc Natl Acad Sci U S A. 2014; 111(3):1102-7 [PubMed] Free Access to Full Article Related Publications
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.

Ding J, Romani J, Zaborski M, et al.
Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2.
PLoS One. 2013; 8(12):e83510 [PubMed] Free Access to Full Article Related Publications
Chronic myeloid leukemia (CML) is a cytogenetic disorder resulting from formation of the Philadelphia chromosome (Ph), that is, the t(9;22) chromosomal translocation and the formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI), such as imatinib and nilotinib, have emerged as leading compounds with which to treat CML. t(9;22) is not restricted to CML, 20-30% of acute lymphoblastic leukemia (ALL) cases also carry the Ph. However, TKIs are not as effective in the treatment of Ph+ ALL as in CML. In this study, the Ph+ cell lines JURL-MK2 and SUP-B15 were used to investigate TKI resistance mechanisms and the sensitization of Ph+ tumor cells to TKI treatment. The annexin V/PI (propidium iodide) assay revealed that nilotinib induced apoptosis in JURL-MK2 cells, but not in SUP-B15 cells. Since there was no mutation in the tyrosine kinase domain of BCR-ABL1 in cell line SUP-B15, the cells were not generally unresponsive to TKI, as evidenced by dephosphorylation of the BCR-ABL1 downstream targets, Crk-like protein (CrkL) and Grb-associated binder-2 (GAB2). Resistance to apoptosis after nilotinib treatment was accompanied by the constitutive and nilotinib unresponsive activation of the phosphoinositide 3-kinase (PI3K) pathway. Treatment of SUP-B15 cells with the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235 alone induced apoptosis in a low percentage of cells, while combining nilotinib and BEZ235 led to a synergistic effect. The main role of PI3K/mTOR inhibitor BEZ235 and the reason for apoptosis in the nilotinib-resistant cells was the block of the translational machinery, leading to the rapid downregulation of the anti-apoptotic protein MDM2 (human homolog of the murine double minute-2). These findings highlight MDM2 as a potential therapeutic target to increase TKI-mediated apoptosis and imply that the combination of PI3K/mTOR inhibitor and TKI might form a novel strategy to combat TKI-resistant BCR-ABL1 positive leukemia.

Chang X, Shi L, Gao F, et al.
Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas.
Neurosurg Focus. 2013; 35(6):E3 [PubMed] Related Publications
OBJECT: Meningiomas are among the most common primary adult brain tumors. Although typically benign, roughly 2%-5% display malignant pathological features. The key molecular pathways involved in malignant transformation remain to be determined.
METHODS: Illumina expression microarrays were used to assess gene expression levels, and Illumina single-nucleotide polymorphism arrays were used to identify copy number variants in benign, atypical, and malignant meningiomas (19 tumors, including 4 malignant ones). The authors also reanalyzed 2 expression data sets generated on Affymetrix microarrays (n = 68, including 6 malignant ones; n = 56, including 3 malignant ones). A weighted gene coexpression network approach was used to identify coexpression modules associated with malignancy.
RESULTS: At the genomic level, malignant meningiomas had more chromosomal losses than atypical and benign meningiomas, with average length of 528, 203, and 34 megabases, respectively. Monosomic loss of chromosome 22 was confirmed to be one of the primary chromosomal level abnormalities in all subtypes of meningiomas. At the transcriptome level, the authors identified 23 coexpression modules from the weighted gene coexpression network. Gene functional enrichment analysis highlighted a module with 356 genes that was highly related to tumorigenesis. Four intramodular hubs within the module (GAB2, KLF2, ID1, and CTF1) were oncogenic in other cancers such as leukemia. A putative meningioma tumor suppressor MN1 was also identified in this module with differential expression between malignant and benign meningiomas.
CONCLUSIONS: The authors' genomic and transcriptome analysis of meningiomas provides novel insights into the molecular pathways involved in malignant transformation of meningiomas, with implications for molecular heterogeneity of the disease.

Huang YJ, Frazier ML, Zhang N, et al.
Reverse-phase protein array analysis to identify biomarker proteins in human pancreatic cancer.
Dig Dis Sci. 2014; 59(5):968-75 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in the United States. The high mortality rate of patients with pancreatic cancer is primarily due to the difficulty of early diagnosis and a lack of effective therapies. There is an urgent need to discover novel molecular targets for early diagnosis and new therapeutic approaches to improve the clinical outcome of this deadly disease.
AIM: We utilized the reverse-phase protein assay (RPPA) to identify differentially expressed biomarker proteins in tumors and matched adjacent, normal-appearing tissue samples from 15 pancreatic cancer patients.
METHODS: The antibody panel used for the RPPA included 130 key proteins involved in various cancer-related pathways. The paired t test was used to determine the significant differences between matched pairs, and the false discovery rate-adjusted p values were calculated to take into account the effect of multiple comparisons.
RESULTS: After correcting for multiple comparisons, we found 19 proteins that had statistically significant differences in expression between matched pairs. However, only four (AKT, β-catenin, GAB2, and PAI-1) of them met the conservative criteria (both a q value <0.05 and a fold-change of ≥3/2 or ≤2/3) to be considered differentially expressed. Overexpression of AKT, β-catenin, and GAB2 in pancreatic cancer tissues identified by RPPA has also been further confirmed by western blot analysis. Further analysis identified several significantly associated canonical pathways and overrepresented network functions.
CONCLUSION: GAB2, a newly identified protein in pancreatic cancer, may provide additional insight into this cancer's pathogenesis. Future studies in a larger population are warranted to further confirm our results.

Davis SJ, Sheppard KE, Pearson RB, et al.
Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer.
Clin Cancer Res. 2013; 19(6):1411-21 [PubMed] Related Publications
PURPOSE: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors.
EXPERIMENTAL DESIGN: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly amplified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene overexpression.
RESULTS: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts.
CONCLUSION: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors.

Yang Y, Wu J, Demir A, et al.
GAB2 induces tumor angiogenesis in NRAS-driven melanoma.
Oncogene. 2013; 32(31):3627-37 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2(WT) and NRAS(G12D) in melanocytes and in melanoma cells increased anchorage-independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1α and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non-linear and non-redundant in melanocytes and melanoma, and thus are acting independent of each other. Finally, we establish a link between GAB2 and angiogenesis in melanoma for the first time. In conclusion, our findings provide evidence that GAB2 is a novel regulator of tumor angiogenesis in NRAS-driven melanoma through regulation of HIF-1α and VEGF expressions mediated by RAS-RAF-MEK-ERK signaling.

Zhang X, Zhang Y, Tao B, et al.
Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2/STAT6 pathway.
FASEB J. 2012; 26(11):4603-13 [PubMed] Related Publications
Goblet cell hyperplasia (GCH) and mucous hypersecretion are common pathological features of chronic pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Despite numerous studies, the molecular basis for this condition remains elusive. Gab2 is a member of the Dos/Gab subfamily scaffolding molecules and plays important roles in regulating growth, differentiation, and inflammation. We found that an elevated level of Gab2 correlates with up-regulated mucus in airway epithelia from patients with lung cancer or COPD, suggesting the potential involvement of Gab2 in pathological lesions in lungs. Knockdown of Gab2 in human airway epithelial cells in vitro decreases IL-13-induced expression of mucin genes. To address the in vivo role of Gab2 in lungs, Gab2-knockout (Gab2(-/-)) mice were sensitized and challenged with ovalbumin (OVA). Further analysis of lungs in an OVA-induced allergy model suggested that GCH and mucus production are remarkably reduced in Gab2(-/-) mice. Mechanistically, Gab2 positively regulates IL-13-induced activation of TYK2/STAT6 by decreasing SOCS3-mediated degradation of TYK2. Together, we define a novel role for Gab2 in mediating mucin gene expression and GCH; these findings have important implications for the pathogenesis and therapy of airway inflammatory diseases.

Ortiz-Padilla C, Gallego-Ortega D, Browne BC, et al.
Functional characterization of cancer-associated Gab1 mutations.
Oncogene. 2013; 32(21):2696-702 [PubMed] Related Publications
Grb2-associated binder 1 (Gab1) is a docking protein that transduces signals from a variety of tyrosine kinases, including Met and the epidermal growth factor receptor (EGFR). Although the related protein Gab2 is strongly implicated in human cancer, a role for Gab1 has been less clear. However, a screen for gene mutations in breast cancer identified two somatic mutations in Gab1, Y83C and T387N. In this paper we describe the functional characterization of these Gab1 mutants. MCF-10A immortalized mammary epithelial cells overexpressing Gab1 Y83C and T387N exhibited a more elongated, fibroblastic phenotype compared with wild-type Gab1 controls. Expression of Gab1 or the mutants promoted epidermal growth factor (EGF)-independent proliferation in monolayer culture to a similar degree. However, in Matrigel culture, both mutants enhanced the formation of acini exhibiting an aberrant, branched morphology. In addition, expression of the mutants modestly increased Erk activation. The two mutants also enhanced branching morphogenesis in a different mammary epithelial cell line, HC11. To gain further insights into the mechanism of action of these mutations, we mapped Gab1 phosphorylation sites by mass spectrometry. This detected phosphorylation of T387 but ;not Y83. Cellular stimulation with EGF or hepatocyte growth factor (HGF) led to a transient, or sustained, induction of T387 phosphorylation, respectively. As T387 corresponds in position to Gab2 T391, which suppresses Gab2 signaling in a phosphorylation-dependent manner, these data support a model in which the T387N mutation abrogates negative-feedback regulation of Gab1. Interrogation of publically-available databases revealed additional cancer-associated mutations at, or in close proximity to, identified serine/threonine phosphorylation sites in other docking proteins. These data indicate that aberrant Gab1 signaling can directly contribute to breast cancer progression, and that negative feedback sites in docking proteins can be targeted by oncogenic mutations.

Quintás-Cardama A, Qiu YH, Post SM, et al.
Reverse phase protein array profiling reveals distinct proteomic signatures associated with chronic myeloid leukemia progression and with chronic phase in the CD34-positive compartment.
Cancer. 2012; 118(21):5283-92 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND: Chronic myeloid leukemia (CML) is a clonal stem cell malignancy whose pathogenesis is driven by constitutive activation of the breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) kinase. Although BCR-ABL1 activation is present in all patients with CML, patients can present in 3 different phases characterized by an increasingly worse prognosis and diminished responsiveness to tyrosine kinase inhibitors: chronic phase, accelerated phase, or blastic phase. The biologic basis for progression from chronic phase to blastic phase and for regulating the homeostasis of tyrosine kinase inhibitor-resistant CML stem cells is not entirely understood.
METHODS: To shed some light into these aspects of CML biology, the authors used reverse phase protein arrays probed with 112 individual monoclonal antibodies to compare protein expression patterns in 40 samples of leukemia-enriched fractions from patients with CML (25 in chronic phase, 5 in accelerated phase, and 10 in phase).
RESULTS: An analysis of variance (significance cutoff, P < .01) unveiled a set of proteins that were overexpressed in blastic phase, including heat-shock protein 90 (hsp90); retinoblastoma (Rb); apoptosis-inducing factor (AIF); serine/threonine-protein phosphatase 2A (PP2A); B-cell leukemia 2 (Bcl-2); X-linked inhibitor of apoptosis protein (Xiap); human homolog of Drosophila Mad (mothers against decapentaplegic) and related Caenorhabditis elegans gene Sma, family member 1 (Smad1); single-stranded DNA binding protein 2 alpha (SSBP2α); poly(adenosine diphosphate-ribose) polymerase (PARP); GRB2-associated binding protein 2 (Gab2); and tripartite motif containing 24 (Trim24). It is noteworthy that several of these proteins also were overexpressed in the CD34-positive compartment, which putatively contains the CML stem cell population.
CONCLUSIONS: The results from this study indicated that reverse phase protein array analysis can unveil differentially expressed proteins in advanced phase CML that can be exploited therapeutically with targeted approaches.

Gadd S, Beezhold P, Jennings L, et al.
Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study.
J Pathol. 2012; 228(1):119-30 [PubMed] Related Publications
Infantile fibrosarcoma (IFS; also known as cellular congenital mesoblastic nephroma, CMN, when in the kidney) is a rare, undifferentiated tumour often characterized by the ETV6-NTRK3 fusion transcript. Our goal was to identify downstream pathways, diagnostic markers and potential therapeutic targets for IFS/CMN. Global gene expression, reverse-phase protein array and ETV6-NTRK3 fusion analyses were performed on 14 IFS/CMN and compared with 41 other paediatric renal tumours. These analyses confirm significant receptor tyrosine kinase (RTK) activation, with evidence of PI3-Akt, MAPK and SRC activation. In particular, GAB2 docking protein, STAT5-pTyr-694, STAT3-pSer-729 and YAP-pSer-127 were elevated, and TAZ-pSer-89 was decreased. This provides mRNA and proteomic evidence that GAB2, STAT activation and phosphorylation of the Hippo pathway transcription co-activators YAP and TAZ contribute to the RTK signal transduction in IFS/CMN. All IFS/CMN tumours displayed a distinctive gene expression pattern that may be diagnostically useful. Unexpectedly, abundant ETV6-NTRK3 transcript copies were present in only 7/14 IFS, with very low copy number in 3/14. An additional 4/14 were negative by RT-PCR and absence of ETV6-NTRK3 was confirmed by FISH for both ETV6 and NTRK3. Therefore, molecular mechanisms other than ETV6-NTRK3 fusion are responsible for the development of some IFS/CMNs and the absence of ETV6-NTRK3 fusion products should not exclude IFS/CMN as a diagnosis.

Wang Y, Sheng Q, Spillman MA, et al.
Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells.
Oncogene. 2012; 31(20):2512-20 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Ovarian cancer, the most deadly gynecologic malignancy, is often diagnosed late and at the advanced stage when the cancer cells have already migrated and invaded into other tissues and organs. Better understanding of the mechanism of metastasis in ovarian cancer cells is essential to the design of effective therapy. In this study, we investigated the function of scaffolding adaptor protein Gab2 in ovarian cancer cells. Gab2 is found to be overexpressed in a subset of ovarian tumors and cancer cell lines. Gab2 expression mainly regulates the migratory behaviors of ovarian cancer cells. Overexpression of Gab2 promotes the migration and invasion, and downregulates E-cadherin expression in ovarian cancer cells with low-Gab2 expression. Conversely, knockdown of Gab2 expression inhibits the migration and invasion, and promotes E-cadherin expression in ovarian cancer cells with high-Gab2 expression. By expressing Gab2 wild-type and Gab2 mutants that are defective in activation of the PI3K and Shp2-Erk pathways, we find that Gab2 inhibits E-cadherin expression and enhances the expression of Zeb1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway. Knockdown of Zeb1 expression blocks Gab2-induced suppression of E-cadherin expression and increase in cell invasion. LY294002 and GDC-0941, inhibitors of PI3K, or Rapamycin, an inhibitor of PI3K downstream target mTOR, can reverse the effects of Gab2 on migration and invasion. Overall, our studies reveal that Gab2 overexpression, via activation of the PI3K-Zeb1 pathway, promotes characteristics of EMT in ovarian cancer cells.

Karlsson E, Waltersson MA, Bostner J, et al.
High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1.
Genes Chromosomes Cancer. 2011; 50(10):775-87 [PubMed] Related Publications
The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.

Peng Z, Luo HW, Yuan Y, et al.
Growth of chronic myeloid leukemia cells is inhibited by infection with Ad-SH2-HA adenovirus that disrupts Grb2-Bcr-Abl complexes.
Oncol Rep. 2011; 25(5):1381-8 [PubMed] Related Publications
The persistence of Bcr-Abl-positive cells in patients on imatinib therapy indicates that inhibition of the Bcr-Abl kinase activity alone might not be sufficient to eradicate the leukemia cells. Many downstream effectors of Bcr-Abl have been described, including activation of both the Grb2-SoS-Ras-MAPK and Grb2-Gab2-PI3K-Akt pathways. The Bcr-Abl-Grb2 interaction, which is mediated by the direct interaction of the Grb2 SH2 domain with the phospho-Bcr-Abl Y177, is required for activation of these signaling pathways. Therefore, disrupting their interaction represents a potential therapeutic strategy for inhibiting the oncogenic downstream signals of Bcr-Abl. Adenovirus Ad-SH2-HA expressing the Grb2 SH2 domain was constructed and applied in this study. As expected, Ad-SH2-HA efficiently infected CML cells and functioned by binding to the phospho-Bcr-Abl Y177 site, competitively disrupting the Grb2 SH2-phospho-Bcr-Abl Y177 complex. They induced potent anti-proliferation and apoptosis-inducing effects in CML cell lines. Moreover, the Ras, MAPK and Akt activities were significantly reduced in the Ad-SH2-HA treated cells. These were not observed with the point-mutated control adenovirus Ad-Sm-HA with abolished phospho-Bcr-Abl Y177 binding sites. These data indicate that, in addition to the direct targeting of Bcr-Abl, selective inhibition of its downstream signaling pathways may be a therapeutic option for CML, and the Ad-SH2-HA-mediated killing strategy could be explored as a promising anti-leukemia agent in CML.

Herrera Abreu MT, Hughes WE, Mele K, et al.
Gab2 regulates cytoskeletal organization and migration of mammary epithelial cells by modulating RhoA activation.
Mol Biol Cell. 2011; 22(1):105-16 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
The docking protein Gab2 is overexpressed in several human malignancies, including breast cancer, and is associated with increased metastatic potential. Here we report that Gab2 overexpression in MCF-10A mammary epithelial cells led to delayed cell spreading, a decrease in stress fibers and mature focal adhesions, and enhanced cell migration. Expression of a Gab2 mutant uncoupled from 14-3-3-mediated negative feedback (Gab2(2xA)) led to a more mesenchymal morphology and acquisition of invasive potential. Expression of either Gab2 or Gab2(2xA) led to decreased activation of RhoA, but only the latter increased levels of Rac-GTP. Expression of constitutively active RhoA in MCF-10A/Gab2 cells restored stress fibers and focal adhesions, indicating that Gab2 signals upstream of RhoA to suppress these structures. Mutation of the two Shp2-binding sites to phenylalanine (Gab2(ΔShp2)) markedly reduced the effects of Gab2 on cellular phenotype and RhoA activation. Expression of Gab2 or Gab2(2xA), but not Gab2(ΔShp2), promoted Vav2 phosphorylation and plasma membrane recruitment of p190A RhoGAP. Knockdown of p190A RhoGAP reversed Gab2-mediated effects on stress fibers and focal adhesions. The identification of a novel pathway downstream of Gab2 involving negative regulation of RhoA by p190A RhoGAP sheds new light on the role of Gab2 in cancer progression.

Fleuren ED, O'Toole S, Millar EK, et al.
Overexpression of the oncogenic signal transducer Gab2 occurs early in breast cancer development.
Int J Cancer. 2010; 127(6):1486-92 [PubMed] Related Publications
Gab2, a docking-type signaling protein with demonstrated oncogenic potential, is overexpressed in breast cancer, but its prognostic significance and role in disease evolution remain unclear. Immunohistochemical detection of Gab2 in a large cohort of primary human breast cancers of known outcome revealed that while Gab2 expression was positively correlated with increased tumor grade, it did not correlate with disease recurrence or breast cancer-related death in the total cohort or in patients stratified according to lymph node, estrogen receptor (ER) or HER2 status. Interestingly, analysis of a "progression series" that included premalignant and preinvasive breast lesions as well as samples of metastatic disease revealed that Gab2 expression was significantly enhanced in the earliest lesion examined, usual ductal hyperplasia, with a further increase detected in ductal carcinoma in situ (DCIS). Furthermore, expression was less in invasive cancers and lymph node metastases than in DCIS, but still higher than in normal breast. These findings indicate that while Gab2 expression is not prognostic in breast cancer, its role in early disease evolution warrants further analysis, as Gab2 and its effectors may provide targets for novel strategies aimed at preventing breast cancer development.

Bocanegra M, Bergamaschi A, Kim YH, et al.
Focal amplification and oncogene dependency of GAB2 in breast cancer.
Oncogene. 2010; 29(5):774-9 [PubMed] Related Publications
DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention.

Mira A, Isella C, Renzulli T, et al.
The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer.
Oncogene. 2009; 28(50):4444-55 [PubMed] Related Publications
Acquisition of independence from anchorage to the extracellular matrix is a critical event for onset and progression of solid cancers. To identify and characterize new genes conferring anchorage independence, we transduced MCF10A human normal breast cells with a retroviral cDNA expression library and selected them by growth in suspension. Microarray analysis targeted on library-derived transcripts revealed robust and reproducible enrichment, after selection, of cDNAs encoding the scaffolding adaptor Gab2. Gab2 was confirmed to strongly promote anchorage-independent growth when overexpressed. Interestingly, downregulation by RNA interference of endogenous Gab2 in neoplastic cells did not affect their adherent growth, but abrogated their growth in soft agar. Gab2-driven anchorage independence was found to specifically involve activation of the Src-Stat3 signaling axis. A transcriptional 'signature' of 205 genes was obtained from GAB2-transduced, anchorage-independent MCF10A cells, and found to contain two main functional modules, controlling proliferation and cell adhesion/migration/invasion, respectively. Extensive validation on breast cancer data sets showed that the GAB2 signature provides a robust prognostic classifier for breast cancer metastatic relapse, largely independent from existing clinical and genomic indicators and from estrogen receptor status. This work highlights a pivotal role for GAB2 and its transcriptional targets in anchorage-independent growth and breast cancer metastatic progression.

Chernoff KA, Bordone L, Horst B, et al.
GAB2 amplifications refine molecular classification of melanoma.
Clin Cancer Res. 2009; 15(13):4288-91 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
PURPOSE: Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas. We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT.
EXPERIMENTAL DESIGN: A total of 85 melanomas arising from sun-protected (n = 23) and sun-exposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-function mutations in BRAF, NRAS, and KIT.
RESULTS: GAB2 amplifications were found in 9% of the cases and were associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2, 13% for KIT, 30% for BRAF, and 4% for NRAS. Importantly, the majority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT.
CONCLUSIONS: GAB2 amplification is critical for melanomas arising from sun-protected sites. Genetic alterations in GAB2 will help refine the molecular classification of melanomas.

Bonuccelli G, Casimiro MC, Sotgia F, et al.
Caveolin-1 (P132L), a common breast cancer mutation, confers mammary cell invasiveness and defines a novel stem cell/metastasis-associated gene signature.
Am J Pathol. 2009; 174(5):1650-62 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Here we used the Met-1 cell line in an orthotopic transplantation model in FVB/N mice to dissect the role of the Cav-1(P132L) mutation in human breast cancer. Identical experiments were performed in parallel with wild-type Cav-1. Cav-1(P132L) up-regulated the expression of estrogen receptor-alpha as predicted, because only estrogen receptor-alpha-positive patients have been shown to harbor Cav-1(P132L) mutations. In the context of primary tumor formation, Cav-1(P132L) behaved as a loss-of-function mutation, lacking any tumor suppressor activity. In contrast, Cav-1(P132L) caused significant increases in cell migration, invasion, and experimental metastasis, consistent with a gain-of-function mutation. To identify possible molecular mechanism(s) underlying this invasive gain-of-function activity, we performed unbiased gene expression profiling. From this analysis, we show that the Cav-1(P132L) expression signature contains numerous genes that have been previously associated with cell migration, invasion, and metastasis. These include i) secreted growth factors and extracellular matrix proteins (Cyr61, Plf, Pthlh, Serpinb5, Tnc, and Wnt10a), ii) proteases that generate EGF and HGF (Adamts1 and St14), and iii) tyrosine kinase substrates and integrin signaling/adapter proteins (Akap13, Cdcp1, Ddef1, Eps15, Foxf1a, Gab2, Hs2st1, and Itgb4). Several of the P132L-specific genes are also highly expressed in stem/progenitor cells or are associated with myoepithelial cells, suggestive of an epithelial-mesenchymal transition. These results directly support clinical data showing that patients harboring Cav-1 mutations are more likely to undergo recurrence and metastasis.

Horst B, Gruvberger-Saal SK, Hopkins BD, et al.
Gab2-mediated signaling promotes melanoma metastasis.
Am J Pathol. 2009; 174(4):1524-33 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.1. Gab2 is an adaptor protein that potentiates the activation of the Ras-Erk and PI3K-Akt pathways and has recently been implicated in human cancer; however, its role in melanoma has not been explored. In this study, we found that Gab2 was either amplified (approximately 11%) and/or overexpressed (approximately 50%) in melanoma. Gab2 protein expression correlated with clinical melanoma progression, and higher levels of expression were seen in metastatic melanomas compared with primary melanoma and melanocytic nevi. We found that overexpression of Gab2 potentiates, whereas silencing of Gab2 reduces, migration and invasion of melanoma cells. Gab2 mediated the hyperactivation of Akt signaling in the absence of growth factors, whereas inhibition of the PI3K-Akt pathway decreased Gab2-mediated tumor cell migration and invasive potential. Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis.

Sun J, Pedersen M, Rönnstrand L
Gab2 is involved in differential phosphoinositide 3-kinase signaling by two splice forms of c-Kit.
J Biol Chem. 2008; 283(41):27444-51 [PubMed] Related Publications
The stem cell factor receptor/c-Kit plays an important physiological role in hematopoiesis, melanogenesis, and gametogenesis. It has also been implicated in numerous human malignancies. Signal transduction pathways shown to be of importance for c-Kit-mediated transformation include the phosphoinositide 3-kinase (PI3K)/Akt pathway. We have previously shown that two alternative splice forms of c-Kit, denoted GNNK(-) and GNNK(+), mediate distinctively different signals. In this study, we found that in the hematopoietic cell line Ba/F3, GNNK(-) c-Kit mediates a substantially stronger activation of PI3K/Akt than GNNK(+) c-Kit. This difference in signaling was shown to be dependent on the association of the scaffolding protein Gab2 with c-Kit, and Src-mediated phosphorylation of Gab2 was shown to be to be independent of the direct association of PI3K with c-Kit. Furthermore, proliferation and survival of Ba/F3 cells expressing a mutant of c-Kit that fails to bind to PI3K directly were slightly decreased compared with wild-type c-Kit-expressing cells. Using small interfering RNA technology, we further verified a role of Gab2 in inducing activation of PI3K/Akt downstream of c-Kit. To summarize, we show that PI3K activation by c-Kit is both splice form-dependent and cell type-specific. Furthermore, activation of PI3K by c-Kit is dependent both on the direct PI3K-binding site in c-Kit and on the phosphorylation of Gab2. The fact that c-Kit has been found mutated in numerous human malignancies, including acute myeloid leukemia, and that Gab2 is often overexpressed in acute myeloid leukemia suggests a potential role of Gab2-mediated PI3K activation in transformation.

Mrózek K
Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype.
Semin Oncol. 2008; 35(4):365-77 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Patients with acute myeloid leukemia (AML) harboring three or more acquired chromosome aberrations in the absence of the prognostically favorable t(8;21)(q22;q22), inv(16)(p13q22)/t(6;16)(p13;q22), and t(15;17)(q22;q21) aberrations form a separate category - AML with a complex karyotype. They constitute 10% to 12% of all AML patents, with the incidence of complex karyotypes increasing with the more advanced age. Recent studies using molecular-cytogenetic techniques (spectral karyotyping [SKY], multiplex fluorescence in situ hybridization [M-FISH]) and array comparative genomic hybridization (a-CGH) considerably improved characterization of previously unidentified, partially identified, or cryptic chromosome aberrations, and allowed precise delineation of genomic imbalances. The emerging nonrandom pattern of abnormalities includes relative paucity, but not absence, of balanced rearrangements (translocations, insertions, or inversions), predominance of aberrations leading to loss of chromosome material (monosomies, deletions, and unbalanced translocations) that involve, in decreasing order, chromosome arms 5q, 17p, 7q, 18q, 16q, 17q, 12p, 20q, 18p, and 3p, and the presence of recurrent, albeit less frequent and often hidden (in marker chromosomes and unbalanced translocations) aberrations leading to overrepresentation of segments from 8q, 11q, 21q, 22q, 1p, 9p, and 13q. Several candidate genes have been identified as targets of genomic losses, for example, TP53, CTNNA1, NF1, ETV6, and TCF4, and amplifications, for example, ERG, ETS2, APP, ETS1, FLI1, MLL, DDX6, GAB2, MYC, TRIB1, and CDX2. Treatment outcomes of complex karyotype patients receiving chemotherapy are very poor. They can be improved to some extent by allogeneic stem cell transplantation in younger patients. It is hoped that better understanding of genomic alterations will result in identification of novel therapeutic targets and improved prognosis in patients with complex karyotypes.

Brown LA, Kalloger SE, Miller MA, et al.
Amplification of 11q13 in ovarian carcinoma.
Genes Chromosomes Cancer. 2008; 47(6):481-9 [PubMed] Related Publications
Amplification at the 11q13 locus is commonly observed in breast, ovarian, head and neck, oral, and esophageal cancer. Studies of this region led to the identification of multiple amplicons containing several potential oncogenes including EMSY, PAK1, RSF1, and GAB2. Here, we investigate the amplification of the above four genes and their prognostic significance in histologically and clinically defined subsets of ovarian cancer. Amplification of all four genes was assessed by fluorescent in situ hybridization in tissue microarrays containing 538 clinically annotated ovarian carcinomas with 12 years of follow-up data. Overall, for the entire cohort, EMSY was amplified in 44 (16%) of 269 cases, PAK1 was amplified in 38 (15%) of 255 cases, RSF1 was amplified in 37 (12%) of 310 cases, and GAB2 was amplified in 41 (16%) of 255 cases. Amplification of EMSY, PAK1, RSF1, and GAB2 were all highly correlated with each other and with a serous histology. Univariate survival analysis showed that tumors with EMSY and RSF1 amplification were associated with a significantly worse outcome. A molecular inversion probe array was then used to study the 11q13 amplicon in 33 high grade serous carcinomas. The core of the amplicon mapped to a 6-Mb region encompassing EMSY, PAK1, RSF1, and GAB2. However, a second more telomeric amplicon was also observed for which no candidate genes have been identified. In summary, amplification of these four putative oncogenes from 11q13 in early ovarian cancer is associated with a serous histology and in the case of EMSY and RSF1 a poor outcome. These findings support the hypothesis that the11q13 amplicon in ovarian cancer is likely driven by a cassette of genes rather than by a single oncogene. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Wu J, Meng F, Lu H, et al.
Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells.
Blood. 2008; 111(7):3821-9 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Lyn kinase functions as a regulator of imatinib sensitivity in chronic myelogenous leukemia (CML) cells through an unknown mechanism. In patients who fail imatinib therapy but have no detectable BCR-ABL kinase mutation, we detected persistently activated Lyn kinase. In imatinib-resistant CML cells and patients, Lyn activation is BCR-ABL independent, it is complexed with the Gab2 and c-Cbl adapter/scaffold proteins, and it mediates persistent Gab2 and BCR-ABL tyrosine phosphorylation in the presence or absence of imatinib. Lyn silencing or inhibition is necessary to suppress Gab2 and BCR-ABL phosphorylation and to recover imatinib activity. Lyn also negatively regulates c-Cbl stability, whereas c-Cbl tyrosine phosphorylation is mediated by BCR-ABL. These results suggest that Lyn exists as a component of the BCR-ABL signaling complex and, in cells with high Lyn expression or activation, BCR-ABL kinase inhibition alone (imatinib) is not sufficient to fully disengage BCR-ABL-mediated signaling and suggests that BCR-ABL and Lyn kinase inhibition are needed to prevent or treat this form of imatinib resistance.

Yuan Y, Qin L, Liu D, et al.
Genetic screening reveals an essential role of p27kip1 in restriction of breast cancer progression.
Cancer Res. 2007; 67(17):8032-42 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
The genetic changes and mechanisms underlying the progression of estrogen-dependent breast cancers to estrogen-independent, antiestrogen-resistant, and metastatic breast cancers are unclear despite being a major problem in endocrine therapy. To identify genes responsible for this progression, we carried out a genetic screening by an enhanced retroviral mutagen (ERM)-mediated random mutagenesis in the estrogen-dependent T47D breast cancer cells. We found that T47D cells contain only one p27kip1 (p27) allele coding for the p27 cyclin-dependent kinase (CDK) inhibitor. An ERM insertion into the p27 locus of T47D cells disrupted the p27 gene and created estrogen-independent and antiestrogen-resistant breast cancer cells that still maintained functional estrogen receptors. Disruption of p27 in T47D cells resulted in several changes, and most of these changes could be rescued by p27 restoration. First, CDK2 activity was increased in the absence of estrogen or in the presence of estrogen antagonists tamoxifen or ICI 182780; second, amplified in breast cancer 1 (AIB1), a cancer overexpressed transcriptional coactivator, was hyperphosphorylated, which made AIB1 a better coactivator for E2F1; and third, growth factor receptor binding protein 2-associated binder 2 (Gab2) and Akt activity were increased following E2F1 overactivation, leading to a significant enhancement of cell migration and invasion. Furthermore, the p27-deficient cells, but not T47D control cells, developed lung metastasis in an ovarian hormone-independent manner when they were i.v. injected into nude mice. In sum, loss of p27 activated AIB1, E2F1, Gab2, and Akt; increased cell migration and invasion; caused antiestrogen insensitivity; and promoted metastasis of breast cancer cells. These findings suggest that p27 plays an essential role in restriction of breast cancer progression.

Voena C, Conte C, Ambrogio C, et al.
The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration.
Cancer Res. 2007; 67(9):4278-86 [PubMed] Related Publications
Anaplastic large cell lymphomas (ALCL) are mainly characterized by the reciprocal translocation t(2;5)(p23;q35) that involves the anaplastic lymphoma kinase (ALK) gene and generates the fusion protein NPM-ALK with intrinsic tyrosine kinase activity. NPM-ALK triggers several signaling cascades, leading to increased cell growth, resistance to apoptosis, and changes in morphology and migration of transformed cells. To search for new NPM-ALK interacting molecules, we developed a mass spectrometry-based proteomic approach in HEK293 cells expressing an inducible NPM-ALK and identified the tyrosine phosphatase Shp2 as a candidate substrate. We found that NPM-ALK was able to bind Shp2 in coprecipitation experiments and to induce its phosphorylation in the tyrosine residues Y542 and Y580 both in HEK293 cells and ALCL cell lines. In primary lymphomas, antibodies against the phosphorylated tyrosine Y542 of Shp2 mainly stained ALK-positive cells. In ALCL cell lines, Shp2-constitutive phosphorylation was dependent on NPM-ALK, as it significantly decreased after short hairpin RNA (shRNA)-mediated NPM-ALK knock down. In addition, only the constitutively active NPM-ALK, but not the kinase dead NPM-ALK(K210R), formed a complex with Shp2, Gab2, and growth factor receptor binding protein 2 (Grb2), where Grb2 bound to the phosphorylated Shp2 through its SH2 domain. Shp2 knock down by specific shRNA decreased the phosphorylation of extracellular signal-regulated kinase 1/2 and of the tyrosine residue Y416 in the activation loop of Src, resulting in impaired ALCL cell proliferation and growth disadvantage. Finally, migration of ALCL cells was reduced by Shp2 shRNA. These findings show a direct involvement of Shp2 in NPM-ALK lymphomagenesis, highlighting its critical role in lymphoma cell proliferation and migration.

Katoh M, Katoh M
FGF signaling network in the gastrointestinal tract (review).
Int J Oncol. 2006; 29(1):163-8 [PubMed] Related Publications
Fibroblast growth factor (FGF) signals are transduced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS-RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS approximately MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K approximately AKT signaling cascade in cell survival and cell fate determination, and the PI3K approximately aPKC signaling cascade in cell polarity control. FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, while recombinant FGF2 protein and FGF4 expression vector are applicable for therapeutic angiogenesis. Helicobacter pylori, a causative pathogen for peptic ulcer diseases, chronic atrophic gastritis and gastric cancer, injects bacterial proteins into gastric epithelial cells by using Type IV secretion system, which leads to FGF signaling activation through FGF2 upregulation as well as CagA-dependent SHP2 activation. FGFR2 gene is preferentially amplified and overexpressed in diffuse-type gastric cancer. PD173074 is a small-molecule inhibitor for FGFR, while RO4396686 and SU6668 are small-molecule inhibitors for FGFR and other tyrosine kinases. Cocktail therapy using multiple protein kinase inhibitors could enhance the therapeutic effects for gastrointestinal cancer through the reduction of recurrence associated with somatic mutations of drug-target genes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding FGF signaling molecules will be identified as novel risk factors of gastrointestinal cancer. Personalized prevention and personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of cancer patients.

Zatkova A, Schoch C, Speleman F, et al.
GAB2 is a novel target of 11q amplification in AML/MDS.
Genes Chromosomes Cancer. 2006; 45(9):798-807 [PubMed] Related Publications
Chromosome arm 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are rare but recurrent aberrations in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We have recently shown that in addition to the MLL core amplicon, independent sequences in 11q23-24 and/or 11q13.5 are coamplified within the same cytogenetic markers in 90% and 60% of patients, respectively. Here we further narrow down the minimal amplicon in 11q13.5 to 1.17 Mb by means of semi-quantitative PCR and FISH analyses. The newly defined amplicon contains seven genes, including the GRB2-associated binding protein 2 (GAB2). Using real-time RT-PCR we show a significant transcriptional upregulation of GAB2 in the patients who have GAB2 coamplified with MLL. Thus, the adaptor molecule GAB2 that has already been shown to enhance oncogenic signaling in other neoplasias appears as a novel target of 11q amplification in AML/MDS.

Bentires-Alj M, Gil SG, Chan R, et al.
A role for the scaffolding adapter GAB2 in breast cancer.
Nat Med. 2006; 12(1):114-21 [PubMed] Related Publications
The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.

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