A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate

Abstract

Migrating cells do not proliferate and vice versa, but the mechanism involved remains unknown. Ghosh et al. reveal how this cellular decision is made by showing that a Gαi–GIV molecular complex interacts with EGF receptor and programs growth factor signaling, triggering migration when assembled and favoring mitosis when assembly is prevented.

Functional characterization of the guanine nucleotide exchange factor (GEF) motif of GIV protein reveals a threshold effect in signaling

“…We have exploited our previous findings on GIV's conserved GEF sequence (8) and its binding sites on the G protein (8,19) to rationally design and characterize specific GIV mutants that impair or enhance its functional coupling to Gαi3 in vitro and in living cells. From the general standpoint, these findings provide insights into how nonreceptor GEFs work, as well as into the role of GIV's GEF function in controlling cell signaling and migration (8,10,13), which is particularly relevant in the context of cancer metastasis (10,17).…”

“…GIV has been previously reported by us (8,14) and others (11,12) to be an enhancer of PI3K-Akt signaling. We previously found that activation of Gαi3 by GIV is required for the efficient activation of Akt upon stimulation of receptor tyrosine kinases (RTKs) (8,10,14,16,19) as well as G-protein-coupled-receptors (GPCRs) (8,19). To further characterize this function, we generated HeLa cell lines stably expressing similar levels of GIV WT or mutants with significantly different GEF activities (Table 1).…”

“…Gα-interacting, vesicleassociated protein, Girdin) is a nonreceptor GEF that activates G proteins via an evolutionarily conserved, well-defined motif (8). A major function of GIV's GEF motif is to enhance the activation of the phosphoinositide 3 kinase (PI3K)-Akt pathway in response to different stimuli (8,(10)(11)(12)(13). GIV has been shown to be essential for cell migration during a variety of physiologic and pathologic processes, i.e., wound healing (14), macrophage chemotaxis (14), tumor cell migration (8,10), neuronal development (12), and endothelial cell migration (15), as well as for inhibiting autophagy (16).…”

“…A major function of GIV's GEF motif is to enhance the activation of the phosphoinositide 3 kinase (PI3K)-Akt pathway in response to different stimuli (8,(10)(11)(12)(13). GIV has been shown to be essential for cell migration during a variety of physiologic and pathologic processes, i.e., wound healing (14), macrophage chemotaxis (14), tumor cell migration (8,10), neuronal development (12), and endothelial cell migration (15), as well as for inhibiting autophagy (16). Importantly, expression of GIV is dysregulated during cancer progression; in poorly metastatic carcinomas, full-length GIV is replaced by a GEF-deficient isoform via alternative splicing whereas, in highly metastatic carcinomas, the full-length isoform of GIV containing the GEF motif is up-regulated, and its expression correlates with decreased patient survival (10,17).…”

The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block

“…Unlike the canonical pathway, where heterotrimeric G proteins engage exclusively with ligand-activated receptor GPCRs, the non-receptor GIV-GEF engages with a diverse array of receptors, including GPCRs, Integrins and RTKs. 26,30,31 and, thereby, enables transactivation of G proteins in response to a wide variety of stimuli (Fig. 1).…”