Regulation of Rho guanine nucleotide exchange factor 3 by phosphorylation in the PH domain
Summary: Although most members of the Rho guanine nucleotide exchange factor (RhoGEF) family are found to be phosphorylated, how phosphorylation regulates RhoGEF function is poorly understood. Here we report the discovery of a mechanism of RhoGEF regulation by phosphorylation. We find that ARHGEF3 i...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225010144 |
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| Summary: | Summary: Although most members of the Rho guanine nucleotide exchange factor (RhoGEF) family are found to be phosphorylated, how phosphorylation regulates RhoGEF function is poorly understood. Here we report the discovery of a mechanism of RhoGEF regulation by phosphorylation. We find that ARHGEF3 is phosphorylated in the pleckstrin homology (PH) domain in a protein kinase C (PKC)-dependent manner. This phosphorylation inhibits ARHGEF3 activation of RhoA and actin stress fiber formation in the cells, and it also disrupts ARHGEF3 binding to PI(3,5)P2 but not to PI(4,5)P2. Guided by molecular dynamics simulation, a mutation in the PH domain is identified to uncouple ARHGEF3 binding to the two lipids, which is used to rule out a role of PI(3,5)P2 in regulating GEF activity. Results of in vitro GEF assays suggest that PH domain phosphorylation diminishes ARHGEF3 catalytic activity, likely through an allosteric mechanism. Our findings reveal a previously unknown type of regulatory mechanism for the family of RhoGEFs. |
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| ISSN: | 2589-0042 |