抗雄激素治疗对转移性前列腺癌的抵抗是一个重大的临床问题。Sema3C通过其受体PlexinB1促进对雄激素撤退的抵抗。PlexinB1的激活促进雄激素受体（AR）的配体独立核转位，可能有助于对雄激素剥夺疗法的抵抗。然而，PlexinB1促进核转位的机制尚不明确。我们在这里展示了PlexinB1和B2通过作为GTP酶活化蛋白（GAP）调节核内转运的关键调节因子Ran的GTP酶活。纯化的PlexinB1/B2蛋白催化RanGTP的水解，而PlexinB1在GAP结构域的突变则抑制了这种活性。Sema4D激活的PlexinB1/B2降低了RanGTP的水平，而PlexinB1或B2减少则增加了细胞中激活的Ran的水平。Ran以GTP依赖方式直接与B型plexin结合。Sema4D通过内吞作用进入细胞内，而PlexinB1和Ran的表达模式重叠。此外，Sema4D/PlexinB1引起的AR核内转位依赖于PlexinB1的GAP结构域，并且被表达非功能性Ran突变体阻断。PlexinB1的减少降低了Ran核/胞质比率，表明较高的RanGTP/GDP比率。Plexins通过其作为RanGAP的活性可能促进雄激素非依赖的前列腺癌的生长。©2023年，作者。

Resistance to anti-androgen therapy for metastatic prostate cancer is a major clinical problem. Sema3C promotes resistance to androgen withdrawal via its receptor, PlexinB1. Activation of PlexinB1 promotes the ligand-independent nuclear translocation of the androgen receptor (AR), which may contribute to resistance to androgen deprivation therapy. However, the mechanism by which PlexinB1 promotes nuclear translocation is unclear. We show here that PlexinB1 and B2 regulate nuclear import by acting as GTPase activating proteins (GAPs) for the small RasGTPase Ran, a key regulator of nuclear trafficking. Purified PlexinB1/B2 protein catalyses the hydrolysis of RanGTP, and mutations in the GAP domain of PlexinB1 inhibit this activity. Activation of PlexinB1/B2 with Sema4D decreases the levels of RanGTP, while PlexinB1 or B2 depletion increases the levels of activated Ran in the cell. Ran directly associates with B-type plexins in a GTP-dependent manner. Sema4D is internalised by endocytosis, and PlexinB1 and Ran display overlapping patterns of expression. Furthermore, Sema4D/PlexinB1-induced AR nuclear translocation is dependent on the GAP domain of PlexinB1 and is blocked by the expression of non-functional Ran mutants. Depletion of PlexinB1 decreases the nuclear/cytoplasmic ratio of Ran, indicative of a higher RanGTP/GDP ratio. Plexins may promote the growth of androgen-independent prostate cancer through their activity as RanGAPs.© 2023. The Author(s).