Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization
Yuxiao Wang1, Huawei He, Nishi Srivastava
1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75063, USA.
Science Signaling
|January 19, 2012
Summary
Plexins act as guanine nucleotide-binding protein (GTPase)-activating proteins (GAPs) for Rap, not R-Ras or M-Ras. Semaphorin binding activates plexin RapGAP activity, crucial for neuronal development.
Area of Science:
- Cell Biology
- Molecular Biology
- Neuroscience
Background:
- Plexins are cell surface receptors mediating semaphorin signals.
- Plexin signaling is thought to involve GTPase-activating protein (GAP) activity for R-Ras and M-Ras.
- Previous studies have failed to detect plexin GAP activity.
Purpose of the Study:
- To investigate the GTPase-activating protein (GAP) activity of plexins.
- To elucidate the mechanism of plexin activation by semaphorins.
- To clarify the role of plexin GAP activity in neuronal development.
Main Methods:
- Purification and biochemical analysis of the plexin cytoplasmic region.
- Crystallographic studies of plexin domains.
- Cell-based assays measuring plexin signaling and neuronal growth cone collapse.
Main Results:
- Purified plexin cytoplasmic region exhibits Rap GTPase-activating protein (GAP) activity via a noncanonical mechanism.
- Plexin RapGAP activity is autoinhibited and activated by dimerization.
- Semaphorin binding activates plexin RapGAP activity in cells, essential for neuronal growth cone collapse.
Conclusions:
- Plexins function as Rap GAPs, challenging previous models.
- Semaphorin-induced activation of plexin RapGAP activity is a key signaling mechanism.
- This pathway is critical for plexin-mediated neuronal development.
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