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Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.

ABSTRACT: GIV/Girdin is a multimodular signal transducer and a bona fide metastasis-related protein. As a guanidine exchange factor (GEF), GIV modulates signals initiated by growth factors (chemical signals) by activating the G protein G?i. Here we report that mechanical signals triggered by the extracellular matrix (ECM) also converge on GIV-GEF via ?1 integrins and that focal adhesions (FAs) serve as the major hubs for mechanochemical signaling via GIV. GIV interacts with focal adhesion kinase (FAK) and ligand-activated ?1 integrins. Phosphorylation of GIV by FAK enhances PI3K-Akt signaling, the integrity of FAs, increases cell-ECM adhesion, and triggers ECM-induced cell motility. Activation of G?i by GIV-GEF further potentiates FAK-GIV-PI3K-Akt signaling at the FAs. Spatially restricted signaling via tyrosine phosphorylated GIV at the FAs is enhanced during cancer metastasis. Thus GIV-GEF serves as a unifying platform for integration and amplification of adhesion (mechanical) and growth factor (chemical) signals during cancer progression.

SUBMITTER: Lopez-Sanchez I

PROVIDER: S-EPMC4666128 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.

Lopez-Sanchez Inmaculada I Kalogriopoulos Nicholas N Lo I-Chung IC Kabir Firooz F Midde Krishna K KK Wang Honghui H Ghosh Pradipta P

Molecular biology of the cell 20151007 24

GIV/Girdin is a multimodular signal transducer and a bona fide metastasis-related protein. As a guanidine exchange factor (GEF), GIV modulates signals initiated by growth factors (chemical signals) by activating the G protein Gαi. Here we report that mechanical signals triggered by the extracellular matrix (ECM) also converge on GIV-GEF via β1 integrins and that focal adhesions (FAs) serve as the major hubs for mechanochemical signaling via GIV. GIV interacts with focal adhesion kinase (FAK) and ...[more]

PMID: 26446841

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Project description:Gα-interacting vesicle-associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimeric G protein Gαi and a bona fide metastasis-related gene that serves as a platform for amplification of tyrosine-based signals via G-protein intermediates. Here we present the first exploratory biomarker study conducted on a cohort of 187 patients with breast cancer to evaluate the prognostic role of total GIV (tGIV) and tyrosine phosphorylated GIV (pYGIV) across the various molecular subtypes. A Kaplan-Meier analysis of recurrence-free survival showed that the presence of tGIV, either cytoplasmic or nuclear, carried poor prognosis, but that nuclear tGIV had a greater prognostic impact (P = 0.007 in early and P = 0.0048 in late clinical stages). Activated pYGIV in the cytoplasm had the greatest prognostic impact in late clinical stages (P = 0.006). Furthermore, we found that the prognostic impacts of cytoplasmic pYGIV and nuclear tGIV were additive (hazard ratio 19.0548; P = 0.0002). Surprisingly, this additive effect of nuclear tGIV/cytoplasmic pYGIV was observed in human epidermal growth factor receptor 2-positive tumors (hazard ratio 16.918; P = 0.0005) but not in triple-negative breast cancers. In triple-negative breast cancers, tGIV and cytoplasmic pYGIV had no prognostic impact; however, membrane-association of pYGIV carried a poor prognosis (P = 0.026). Both tGIV and pYGIV showed no correlation with clinical stage, tumor size, pathologic type, lymph node involvement, and BRCA1/2 status. We conclude that immunocytochemical detection of pYGIV and tGIV can serve as an effective prognosticator. On the basis of the differential prognostic impact of tGIV/pYGIV within each molecular subtype, we propose a diagnostic algorithm. Further studies on larger cohorts are essential to rigorously assess the effectiveness and robustness of this algorithm in prognosticating outcome among patients with breast cancer.-Dunkel, Y., Diao, K., Aznar, N., Swanson, L., Liu, L., Zhu, W., Mi, X.-Y., Ghosh, P. Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.

Dataset Information

Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.

Publications

Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.

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