A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate.
Cells respond to growth factors by either migrating or proliferating, but not both at the same time, a phenomenon termed migration-proliferation dichotomy. The underlying mechanism of this phenomenon has remained unknown. We demonstrate here that Galpha(i) protein and GIV, its nonreceptor guanine nucleotide exchange factor (GEF), program EGF receptor (EGFR) signaling and orchestrate this dichotomy. GIV directly interacts with EGFR, and when its GEF function is intact, a Galpha(i)-GIV-EGFR signaling complex assembles, EGFR autophosphorylation is enhanced, and the receptor's association with the plasma membrane (PM) is prolonged. Accordingly, PM-based motogenic signals (PI3-kinase-Akt and PLCgamma1) are amplified, and cell migration is triggered. In cells expressing a GEF-deficient mutant, the Galphai-GIV-EGFR signaling complex is not assembled, EGFR autophosphorylation is reduced, the receptor's association with endosomes is prolonged, mitogenic signals (ERK 1/2, Src, and STAT5) are amplified, and cell proliferation is triggered. In rapidly growing, poorly motile breast and colon cancer cells and in noninvasive colorectal carcinomas in situ in which EGFR signaling favors mitosis over motility, a GEF-deficient splice variant of GIV was identified. In slow growing, highly motile cancer cells and late invasive carcinomas, GIV is highly expressed and has an intact GEF motif. Thus, inclusion or exclusion of GIV's GEF motif, which activates Galphai, modulates EGFR signaling, generates migration-proliferation dichotomy, and most likely influences cancer progression.
Ghosh
Pradipta
P
Department of Cellular and Molecular Medicine and Medicine, School of Medicine, University of California-San Diego, La Jolla, CA 92093, USA. prghosh@ucsd.edu
Beas
Anthony O
AO
Bornheimer
Scott J
SJ
Garcia-Marcos
Mikel
M
Forry
Erin P
EP
Johannson
Carola
C
Ear
Jason
J
Jung
Barbara H
BH
Cabrera
Betty
B
Carethers
John M
JM
Farquhar
Marilyn G
MG
D000595:Amino Acid Sequence; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D033921:Vesicular Transport Proteins; D066246:ErbB Receptors; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
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