TY - JOUR
T1 - The scaffold RhoGAP protein ARHGAP8/BPGAP1 synchronizes Rac and Rho signaling to facilitate cell migration
AU - Wong, Darren Chen Pei
AU - Pan, Catherine Qiurong
AU - Er, Shi Yin
AU - Thivakar, T.
AU - Rachel, Tan Zi Yi
AU - Seah, Sock Hong
AU - Chua, Pei Jou
AU - Jiang, Tingting
AU - Chew, Ti Weng
AU - Chaudhuri, Parthiv Kant
AU - Mukherjee, Somsubhro
AU - Salim, Agus
AU - Aye, Thike Aye
AU - Koh, Cheng Gee
AU - Lim, Chwee Teck
AU - Tan, Puay Hoon
AU - Bay, Boon Huat
AU - Ridley, Anne J.
AU - Low, Boon Chuan
N1 - Publisher Copyright:
© 2023 Wong, Pan, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution 4.0 International Creative Commons CC-BY 4.0 License (https://creativecommons.org/licenses/by/4.0/).
PY - 2023/3/1
Y1 - 2023/3/1
N2 - 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 EGFRBPGAP1-Vav1-Rac1-RhoA signaling axis for cancer intervention.
AB - 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 EGFRBPGAP1-Vav1-Rac1-RhoA signaling axis for cancer intervention.
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U2 - 10.1091/mbc.E21-03-0099
DO - 10.1091/mbc.E21-03-0099
M3 - Article
C2 - 36598812
AN - SCOPUS:85146993895
SN - 1059-1524
VL - 34
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 3
M1 - ar13
ER -
