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Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta(1) integrin activity
Izumi Oinuma1, Hironori Katoh, Manabu Negishi
1Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
The Journal of Cell Biology
|May 17, 2006
Summary
Semaphorin 4D (Sema4D) binding to Plexin-B1 inhibits cell migration by suppressing R-Ras activation. This mechanism controls beta(1) integrin activity, crucial for cell movement in response to extracellular matrix cues.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Plexins are cell surface receptors for semaphorins, mediating cell migration.
- Plexin-B1 acts as a GTPase-activating protein (GAP) for R-Ras, a regulator of integrin activity and cell migration.
Purpose of the Study:
- To investigate the role of R-Ras downstream of the semaphorin 4D (Sema4D)/Plexin-B1 pathway in cell migration.
- To elucidate how Sema4D/Plexin-B1 signaling modulates R-Ras and beta(1) integrin activation.
Main Methods:
- Characterization of R-Ras function downstream of Sema4D/Plexin-B1.
- Utilizing overexpression of R-Ras-specific GAP and RNA interference for R-Ras knockdown.
- Assessing ECM-dependent activation of R-Ras, phosphatidylinositol 3-kinase, and beta(1) integrin.
Main Results:
- Sema4D binding to Plexin-B1 suppressed ECM-dependent R-Ras activation via its R-Ras GAP domain.
- This suppression led to reduced R-Ras-mediated phosphatidylinositol 3-kinase and beta(1) integrin activation, inhibiting cell migration.
- Inactivation of R-Ras was sufficient to inhibit beta(1) integrin activation and cell migration.
Conclusions:
- R-Ras activity is essential for extracellular matrix-mediated beta(1) integrin activation and cell migration.
- Sema4D/Plexin-B1 signaling inhibits cell migration by inactivating R-Ras through its GAP activity, thereby modulating beta(1) integrin function.
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