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AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.

ABSTRACT: Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress. Expression of an oncogenic mutant of GIV (cataloged in TCGA) that cannot be phosphorylated by AMPK increased anchorage-independent growth of tumor cells and helped these cells to evade the tumor-suppressive action of Metformin. This work defines a fundamental homeostatic mechanism by which the AMPK-GIV axis reinforces cell junctions against stress-induced collapse and also provides mechanistic insight into the tumor-suppressive action of Metformin.

SUBMITTER: Aznar N

PROVIDER: S-EPMC5119889 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.

Aznar Nicolas N Patel Arjun A Rohena Cristina C CC Dunkel Ying Y Joosen Linda P LP Taupin Vanessa V Kufareva Irina I Farquhar Marilyn G MG Ghosh Pradipta P

eLife 20161104

Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening ma ...[more]

PMID: 27813479

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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.

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AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.

Publications

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.

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