A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
RCP-driven alpha 5 beta 1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex
Tekijät: Jacquemet G, Green DM, Bridgewater RE, von Kriegsheim A, Humphries MJ, Norman JC, Caswell PT
Kustantaja: ROCKEFELLER UNIV PRESS
Julkaisuvuosi: 2013
Journal: Journal of Cell Biology
Tietokannassa oleva lehden nimi: JOURNAL OF CELL BIOLOGY
Lehden akronyymi: J CELL BIOL
Vuosikerta: 202
Numero: 6
Aloitussivu: 917
Lopetussivu: 935
Sivujen määrä: 19
ISSN: 0021-9525
DOI: https://doi.org/10.1083/jcb.201302041
Tiivistelmä
Inhibition of alpha v beta 3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rob-coupling protein (RCP)-dependent recycling of alpha 5 beta 1 integrin. RCP and alpha 5 beta 1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent alpha 5 beta 1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of alpha 5 beta 1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.
Inhibition of alpha v beta 3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rob-coupling protein (RCP)-dependent recycling of alpha 5 beta 1 integrin. RCP and alpha 5 beta 1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent alpha 5 beta 1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of alpha 5 beta 1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.
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