A Novel Stat3 Binding Motif in Gab2 Mediates Transformation of Primary Hematopoietic Cells by the Stk/Ron Receptor Tyrosine Kinase in Response to Friend Virus Infection

Ni, Shuang; Zhao, Chen; Feng, Gen Sheng; Paulson, Robert F.; Correll, Pamela H.

doi:10.1128/mcb.01838-06

Cited by 32 publications

(38 citation statements)

References 41 publications

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“…Indeed, Stat3 has already been involved in the Src-and Jak1-driven proliferation of human breast carcinoma cells (Garcia et al, 2001) and in the anchorageindependent growth of cancer cells (Zhang et al, 2006). Moreover, Gab2 was found to contain a functional Stat3-binding motif promoting its recruitment and activation (Ni et al, 2007). Our biochemical data confirmed the contribution of Src and Stat3 to Gab2-mediated anchorage-independent growth: Gab2 expression increased Src and Stat3 phosphorylation both basally and after prolonged suspension culture, and Gab2 downregulation by RNA interference led to the reduction of Src and Stat3 activation not only in MCF10A cells constitutively expressing exogenous Gab2, but also in neoplastic cells losing anchorage independence as a consequence of endogenous Gab2 silencing.…”

Section: Gab2 Promotes Anchorage-independent Growthmentioning

confidence: 99%

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

et al. 2009

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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 anchorageindependent 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, anchorageindependent 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.

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Section: Gab2 Promotes Anchorage-independent Growthmentioning

confidence: 99%

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

et al. 2009

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“…The second analysis found a complex network of 206 objects that was enriched for EGFR signaling pathway members (FDR: P ¼ 4.4 Â 10 À21 ; Supplementary Table S5). These interrelated networks could be explained by the physical interaction of GAB2 with STAT3 (22,23), leading to downstream changes in transcription and the involvement of GAB2 in the receptor tyrosine kinase signaling transduction pathway.…”

Section: Data Mining Identifies Protein Network Associated With Gab2mentioning

confidence: 99%

Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

Davis

Sheppard

Anglesio

et al. 2015

Molecular Cancer Therapeutics

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Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. Mol Cancer Ther; 14(6); 1495–503. ©2015 AACR.

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“…Although we were unable to show definitively that the failure of SFFV gp55-activated sf-Stk to activate STATs 1 and 5 in NIH 3T3 cells was due to the absence of the EpoR in these cells, it remains a likely possibility that activation of these STATs in SFFV-infected erythroid cells is due to the involvement of the EpoR in the disease complex. In contrast to STATs 1 and 5, STAT3 is activated in NIH 3T3/sf-Stk/SFFV cells, suggesting that activation of this STAT may not require the EpoR but may be activated directly by sf-Stk, as occurs with sf-Stk's close relative Met (4) or may be activated downstream of sf-Stk by binding to Gab2 (16).…”

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

“…Insertional activation of PU.1 results in changes that block differentiation of the cells even in the presence of Epo (32). Continuous expression of PU.1 is necessary for maintenance of the transformed phenotype of MEL cells (6,16).Several signaling pathways and molecules are activated downstream of the EpoR after it binds Epo (reviewed in reference 28), and many of these, such as the JAK/STAT, Ras/ Raf/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, are constitutively activated in EpoR-expressing cells infected with Friend SFFV (14,15,19,23). Initially it was thought that constitutive signals from the EpoR primarily drove SFFV-induced hyperplasia.…”

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confidence: 99%

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The Tyrosine Kinase sf-Stk and Its Downstream Signals Are Required for Maintenance of Friend Spleen Focus-Forming Virus-Induced Fibroblast Transformation

Jelacic

Thompson

Hanson

et al. 2008

J Virol

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Infection of erythroid progenitor cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia and eventually to erythroleukemia in susceptible strains of mice. The viral envelope protein, SFFV gp55, forms a complex with the erythropoietin receptor (EpoR) and a short form of the receptor tyrosine kinase Stk (sf-Stk), activating both and inducing Epo-independent proliferation. Recently, we discovered that coexpression of SFFV gp55 and sf-Stk is sufficient to transform NIH 3T3 and primary fibroblasts. In the current study, we demonstrate that sf-Stk and its downstream effectors are critical to this transformation. Unlike SFFV-derived erythroleukemia cells, which depend on PU.1 expression for maintenance of the transformed phenotype, SFFV gp55-sf-Stk-transformed fibroblasts are negative for PU.1. Underscoring the importance of sf-Stk to fibroblast transformation, knockdown of sf-Stk abolished the ability of these cells to form anchorageindependent colonies. Like SFFV-infected erythroid cells, SFFV gp55-sf-Stk-transformed fibroblasts express high levels of phosphorylated MEK, ERK, phosphatidylinositol 3-kinase (PI3K), Gab1/2, Akt, Jun kinase (JNK), and STAT3, but unlike virus-infected erythroid cells they fail to express phosphorylated STATs 1 and 5, which may require involvement of the EpoR. In addition, the p38 mitogen-activated protein kinase (MAPK) stress response is suppressed in the transformed fibroblasts. Inhibition of either JNK or the PI3K pathway decreases both monolayer proliferation and anchorage-independent growth of the transformed fibroblasts as does the putative kinase inhibitor luteolin, but inhibition of p38 MAPK has no effect. Our results indicate that sf-Stk is a molecular endpoint of transformation that could be targeted directly or with agents against its downstream effectors.Friend spleen focus-forming virus (SFFV) is a replicationincompetent murine retrovirus that causes a rapid erythroblastosis when injected into mice with its related helper virus Friend MuLV (reviewed in reference 30). Friend SFFV has deletions in its env gene, which give rise to a unique glycoprotein, SFFV gp55. This unique glycoprotein confers pathogenicity on the virus; a vector encoding SFFV gp55 alone is sufficient to induce erythroblastosis in susceptible strains of mice. The Fv-2 gene encodes one of the key susceptibility factors for SFFV-induced erythroid disease (10, 26). Fv-2, which encodes the receptor tyrosine kinase Stk/RON, is unusual in that it has a second internal promoter, which allows for the transcription of two distinct gene products: full-length Stk and a short form, sf-Stk (8, 26). Full-length Stk is a typical receptor tyrosine kinase with an extracellular ligand binding domain, a transmembrane domain, and an intracellular kinase/ signaling domain. The short form lacks the extracellular ligand binding domain but retains the transmembrane domain and intracellular kinase/signaling domain. Susceptible strains of mice express both full-length Stk and sf-Stk, but resistant strain...

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A Novel Stat3 Binding Motif in Gab2 Mediates Transformation of Primary Hematopoietic Cells by the Stk/Ron Receptor Tyrosine Kinase in Response to Friend Virus Infection

Cited by 32 publications

References 41 publications

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition

The Tyrosine Kinase sf-Stk and Its Downstream Signals Are Required for Maintenance of Friend Spleen Focus-Forming Virus-Induced Fibroblast Transformation

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