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A Gαi–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 Gα(i) protein and GIV, its nonreceptor guanine nucleo...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893996/ https://www.ncbi.nlm.nih.gov/pubmed/20462955 http://dx.doi.org/10.1091/mbc.E10-01-0028 |
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author | Ghosh, Pradipta Beas, Anthony O. Bornheimer, Scott J. Garcia-Marcos, Mikel Forry, Erin P. Johannson, Carola Ear, Jason Jung, Barbara H. Cabrera, Betty Carethers, John M. Farquhar, Marilyn G. |
author_facet | Ghosh, Pradipta Beas, Anthony O. Bornheimer, Scott J. Garcia-Marcos, Mikel Forry, Erin P. Johannson, Carola Ear, Jason Jung, Barbara H. Cabrera, Betty Carethers, John M. Farquhar, Marilyn G. |
author_sort | Ghosh, Pradipta |
collection | PubMed |
description | 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 Gα(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 Gα(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 PLCγ1) are amplified, and cell migration is triggered. In cells expressing a GEF-deficient mutant, the Gαi–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 Gαi, modulates EGFR signaling, generates migration-proliferation dichotomy, and most likely influences cancer progression. |
format | Text |
id | pubmed-2893996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-28939962010-09-16 A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate Ghosh, Pradipta Beas, Anthony O. Bornheimer, Scott J. Garcia-Marcos, Mikel Forry, Erin P. Johannson, Carola Ear, Jason Jung, Barbara H. Cabrera, Betty Carethers, John M. Farquhar, Marilyn G. Mol Biol Cell Articles 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 Gα(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 Gα(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 PLCγ1) are amplified, and cell migration is triggered. In cells expressing a GEF-deficient mutant, the Gαi–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 Gαi, modulates EGFR signaling, generates migration-proliferation dichotomy, and most likely influences cancer progression. The American Society for Cell Biology 2010-07-01 /pmc/articles/PMC2893996/ /pubmed/20462955 http://dx.doi.org/10.1091/mbc.E10-01-0028 Text en © 2010 by The American Society for Cell Biology |
spellingShingle | Articles Ghosh, Pradipta Beas, Anthony O. Bornheimer, Scott J. Garcia-Marcos, Mikel Forry, Erin P. Johannson, Carola Ear, Jason Jung, Barbara H. Cabrera, Betty Carethers, John M. Farquhar, Marilyn G. A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate |
title | A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate |
title_full | A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate |
title_fullStr | A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate |
title_full_unstemmed | A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate |
title_short | A Gαi–GIV Molecular Complex Binds Epidermal Growth Factor Receptor and Determines Whether Cells Migrate or Proliferate |
title_sort | gαi–giv molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893996/ https://www.ncbi.nlm.nih.gov/pubmed/20462955 http://dx.doi.org/10.1091/mbc.E10-01-0028 |
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