足場となるRhoGAPタンパク質ARHGAP8/BPGAP1は、RacとRhoシグナルを同期させ、細胞移動を促進する The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration
Darren Chen Pei Wong,Catherine Qiurong Pan,Shi Yin Er,T. Thivakar,Tan Zi Yi Rachel,Sock Hong Seah,Pei Jou Chua,Tingting Jiang,Ti Weng Chew,Parthiv Kant Chaudhuri,Somsubhro Mukherjee,Agus Salim,Thike Aye Aye,Cheng Gee Koh,Chwee Teck Lim,Puay Hoon Tan,Boon Huat Bay,Anne J. Ridley and Boon Chuan Low
Molecular Biology of the Cell Published:1 Feb 2023
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 prometastatic RhoGAP, ARHGAP8/BPGAP1, binds to inactive Rac1 and localizes to lamellipodia. BPGAP1 recruits the RacGEF Vav1 under epidermal growth factor (EGF) stimulation and activates Rac1, leading to polarized cell motility, spreading, invadopodium formation, and cell extravasation and promotes cancer cell migration. Importantly, BPGAP1 down-regulates 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 signaling in cell motility. As epidermal growth factor receptor (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 signaling axis for cancer intervention.