| Plexin‑B1 is a class B plexin family transmembrane receptor for semaphorins, most prominently Semaphorin‑4D (Sema4D/CD100), that couples extracellular guidance or motility cues to Rho‑family GTPase signaling and integrin‑dependent pathways controlling cytoskeletal organization, migration, and invasive growth in endothelial and epithelial contexts. The receptor displays a large extracellular region with a Sema domain, PSI and IPT repeats that form the Sema4D‑binding interface, a single transmembrane segment, and a cytoplasmic region containing a split GAP domain and binding sites for Rho‑family regulators; ligand engagement by Sema4D induces plexin‑B1 clustering and conformational rearrangements that activate its intracellular signaling modules. Semaphorin‑4D binding to plexin‑B1 on endothelial cells elicits a motile, pro‑angiogenic phenotype characterized by focal adhesion assembly, stress fiber formation, and myosin light chain phosphorylation, and this response depends on activation of RhoA and its effector Rho kinase (ROCK), which drive actomyosin contractility and reorganization of the actin cytoskeleton. Plexin‑B1 signaling also intersects with integrins and receptor tyrosine kinases to propagate downstream cascades: in endothelial cells, plexin‑B1 promotes integrin‑mediated activation of the focal adhesion kinase family member Pyk2, which then stimulates PI3K activity and sequential activation of Akt and ERK, linking semaphorin engagement to survival and mitogenic pathways as well as to cell motility. These signaling events are anchored in the ability of plexin‑B1 to bind and regulate small GTPases; the intracellular domain interacts with RhoA, Rac, and their exchange factors, and prostate‑cancer‑associated mutations in PLXNB1 have been shown to selectively disrupt Rac binding and sequestration, thereby altering Rac‑dependent cell spreading and protrusive activity and changing the balance between RhoA‑ and Rac‑driven cytoskeletal programs. Plexin‑B1 is a key modifier of metastatic behavior: deletion of Plexin‑B1 or prostate‑specific overexpression of wild‑type plexin‑B1 reduces invasion into surrounding stroma and decreases distant metastasis, whereas expression of a patient‑derived mutant form (P1597L) in prostate epithelium markedly increases metastatic spread, particularly to distant organs, and this enhanced invasion correlates with elevated myosin light chain phosphorylation, consistent with hyperactivation of the Rho/ROCK axis downstream of mutant plexin‑B1. Across these contexts, plexin‑B1 functions as a semaphorin‑responsive hub that integrates ligand binding, Rho GTPase regulation, and integrin‑Pyk2–PI3K–Akt/ERK signaling to control cell shape, adhesion dynamics, angiogenic migration, and carcinoma invasiveness, and prostate‑cancer‑linked mutations in PLXNB1 rewire these pathways toward a pro‑metastatic output. |
