Mol Biol Cell. 2023 Jan 4:mbcE21030099. doi: 10.1091/mbc.E21-03-0099. Online ahead of print.
ABSTRACT
Rho GTPases regulate cell morphogenesis and motility under the tight control of guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). However, the underlying mechanism(s) that coordinate their spatiotemporal activities, whether separately or together, remain unclear. We show that a pro-metastatic RhoGAP, ARHGAP8/BPGAP1, binds to inactive Rac1 and localizes to lamellipodia. BPGAP1 recruits the RacGEF Vav1 under EGF stimulation and activates Rac1, leading to polarized cell motility, spreading, invadopodium formation, cell extravasation and promotes cancer cell migration. Importantly, BPGAP1 downregulates local RhoA activity which influences Rac1 binding to BPGAP1 and its subsequent activation by Vav1. Our results highlight the importance of BPGAP1 in recruiting Vav1 and Rac1 to promote Rac1 activation for cell motility. BPGAP1 also serves to control the timing of Rac1 activation with RhoA inactivation via its RhoGAP activity. BPGAP1, therefore, acts as a dual-function scaffold that recruits Vav1 to activate Rac1 while inactivating RhoA to synchronize both Rho and Rac signalling in cell motility. As EGFR, Vav1, RhoA, Rac1 and BPGAP1 are all associated with cancer metastasis, BPGAP1 could provide a crucial checkpoint for the EGFR-BPGAP1-Vav1-Rac1-RhoA signalling axis for cancer intervention. [Media: see text] [Media: see text] [Media: see text].
PMID:36598812 | DOI:10.1091/mbc.E21-03-0099
