Editors' ChoiceCell Biology

Move or Divide?

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Science Signaling  06 Jul 2010:
Vol. 3, Issue 129, pp. ec203
DOI: 10.1126/scisignal.3129ec203

Growth factor receptors, such as the epidermal growth factor receptor (EGFR), can trigger either cell migration or cell division, but generally these two responses are exclusive, a phenomenon called the “migration-proliferation dichotomy.” GIV, a nonreceptor guanine nucleotide exchange factor for Gαi, and Gαi have been implicated in the migratory response to EGF. By analyzing cultured cells (in which endogenous GIV was knocked down) expressing an siRNA-resistant GIV or a GEF-deficient mutant (GIV-FA), Ghosh et al. found that in response to EGF and scratch wounding, cells with the wild-type GIV exhibited a robust migratory response, whereas those expressing GIV-FA exhibited reduced migration but enhanced proliferation. A similar promigratory response was obtained by expressing either Gαi or a constitutively active mutant, and a proliferative response was obtained by expressing an inactivated Gαi. Analysis of the EGFR signaling pathways activated by addition of EGF indicated that GIV promoted migratory signaling events [phosphorylation of the EGFR at sites involved in the activation of Akt and phospholipase Cγ1 (PLCγ1), the phosphorylation and activation of which were also increased] and reduced mitogenic signaling [phosphorylation of the c-Src–dependent site on EGFR and phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the transcription factor STAT5b]. In contrast, the dominant-negative GIV-FA promoted mitogenic signaling and inhibited migratory signaling. In response to EGF, EGFR persisted longer at the plasma membrane in cells with GIV, but its overall stability was reduced, compared to cells with GIV-FA, which showed rapid internalization of EGFR but reduced EGFR degradation. Coimmunoprecipitation and in vitro binding studies showed that EGFR and GIV interacted directly, whereas Gαi associated with this complex indirectly through the GIV GEF domain. Analysis of the poorly invasive, but rapidly dividing, MCF7 (breast cancer–derived cell line) and Ls174T and HT29 (colon cancer cell lines) revealed an alternative splice variant for GIV, which resulted in the production of a truncated protein lacking the C-terminal GEF domain (GIVΔCT). Introduction of GIVΔCT into HeLa cells showed that, in the scratch wound assay, these cells were promitogenic, with enhanced ERK1/2 and STAT5b signaling and reduced receptor degradation, and were poorly motogenic, with reduced Akt and PLCγ1 phosphorylation. The importance of this GIV and the splice variant for cancer progression from dividing to metastatic was revealed by immunohistochemistry of human colorectal cancer samples at various stages. Noninvasive tumors were positive for the short form of GIV but not the GEF-containing form, whereas invasive tumors had the GEF-containing form. These results suggest that whether a cell chooses to respond to EGF with division or migration depends on the recruitment of Gαi to the GIV-EGFR complex.

P. Ghosh, A. O. Beas, S. J. Bornheimer, M. Garcia-Marcos, E. P. Forry, C. Johannson, J. Ear, B. H. Jung, B. Cabrera, J. M. Carethers, M. G. Farquhar, A Gαi-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Mol. Biol. Cell 21, 2338–2354 (2010). [Abstract] [FullText]

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