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Trimeric G Protein Activation by the Non‐Receptor Protein GIV/ Girdin is Required for Integrin Signaling
Author(s) -
Leyme Anthony,
PerezGutierrez Lorena,
Nguyen Lien,
GarciaMarcos Mikel
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.719.5
Subject(s) - signal transduction , integrin , microbiology and biotechnology , g protein coupled receptor , biology , g protein , extracellular matrix , pi3k/akt/mtor pathway , actin cytoskeleton , collagen receptor , guanine nucleotide exchange factor , protein kinase b , receptor , cancer research , cytoskeleton , cell , biochemistry
Signal transduction via both integrins and G protein‐coupled receptors (GPCRs) is critical to control cell behavior in health and disease. These two receptor classes have been traditionally believed to trigger distinct and independent signaling cascades. Here we report a novel mechanism of integrin signal transduction that requires activation of the trimeric G protein Gαi by the non‐receptor Guanine nucleotide Exchange Factor (GEF) GIV (aka Girdin), a pro‐metastatic protein. We demonstrate that GIV is necessary and sufficient to enhance responses to extracellular matrix (ECM) stimulation and make tumor cells more invasive. These responses include remodeling of the actin cytoskeleton and PI3K‐dependent signaling, resulting in enhanced haptotaxis and haptoinvasion. Tumor cells engineered to express GEF‐deficient GIV fail to transduce integrin signals into pro‐invasive cell responses. Mechanistically, we show that GIV and Gαi3 are recruited to integrin complexes upon ECM stimulation and activate a Gβγ‐PI3K‐Akt signaling cascade. In summary, our discoveries delineate a novel mechanism by which integrin signaling is rewired during metastasis to result in increased tumor invasiveness. This work is supported by the American Cancer society (RGS‐13‐362‐01‐TBE), the Elsa U. Pardee Foundation and NIH (R01GM108733).