PMID- 20462955
OWN - NLM
STAT- MEDLINE
DCOM- 20101216
LR  - 20211020
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 21
IP  - 13
DP  - 2010 Jul 1
TI  - A Galphai-GIV molecular complex binds epidermal growth factor receptor and 
      determines whether cells migrate or proliferate.
PG  - 2338-54
AB  - 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.
FAU - Ghosh, Pradipta
AU  - Ghosh P
AD  - Department of Cellular and Molecular Medicine and Medicine, School of Medicine, 
      University of California-San Diego, La Jolla, CA 92093, USA. prghosh@ucsd.edu
FAU - Beas, Anthony O
AU  - Beas AO
FAU - Bornheimer, Scott J
AU  - Bornheimer SJ
FAU - Garcia-Marcos, Mikel
AU  - Garcia-Marcos M
FAU - Forry, Erin P
AU  - Forry EP
FAU - Johannson, Carola
AU  - Johannson C
FAU - Ear, Jason
AU  - Ear J
FAU - Jung, Barbara H
AU  - Jung BH
FAU - Cabrera, Betty
AU  - Cabrera B
FAU - Carethers, John M
AU  - Carethers JM
FAU - Farquhar, Marilyn G
AU  - Farquhar MG
LA  - eng
GR  - R01 DK067287/DK/NIDDK NIH HHS/United States
GR  - R24 DK080506/DK/NIDDK NIH HHS/United States
GR  - DK-I7780/DK/NIDDK NIH HHS/United States
GR  - P30 NS047101/NS/NINDS NIH HHS/United States
GR  - R01 DK067287-04/DK/NIDDK NIH HHS/United States
GR  - R01 CA100768/CA/NCI NIH HHS/United States
GR  - T32 DK-07202/DK/NIDDK NIH HHS/United States
GR  - CA-100768/CA/NCI NIH HHS/United States
GR  - T32 DK007202/DK/NIDDK NIH HHS/United States
GR  - R24 DK080506-03/DK/NIDDK NIH HHS/United States
GR  - DK-80506/DK/NIDDK NIH HHS/United States
GR  - P30 NS-047101/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100512
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (CCDC88A protein, human)
RN  - 0 (Microfilament Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Vesicular Transport Proteins)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
SB  - IM
MH  - Amino Acid Sequence
MH  - Cell Movement/*physiology
MH  - *Cell Proliferation
MH  - ErbB Receptors/genetics/*metabolism
MH  - GTP-Binding Protein alpha Subunits, Gi-Go/genetics/*metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Microfilament Proteins/genetics/*metabolism
MH  - Molecular Sequence Data
MH  - Multiprotein Complexes/*metabolism
MH  - Protein Binding
MH  - Signal Transduction/physiology
MH  - Vesicular Transport Proteins/genetics/*metabolism
PMC - PMC2893996
EDAT- 2010/05/14 06:00
MHDA- 2010/12/17 06:00
PMCR- 2010/09/16
CRDT- 2010/05/14 06:00
PHST- 2010/05/14 06:00 [entrez]
PHST- 2010/05/14 06:00 [pubmed]
PHST- 2010/12/17 06:00 [medline]
PHST- 2010/09/16 00:00 [pmc-release]
AID - E10-01-0028 [pii]
AID - 3604216 [pii]
AID - 10.1091/mbc.e10-01-0028 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2010 Jul 1;21(13):2338-54. doi: 10.1091/mbc.e10-01-0028. Epub 2010 
      May 12.