Effect of cancer-associated mutations in the PlexinB1 gene

Two specific mutations found in prostate cancer enhance RhoD binding and one other mutation results in loss of inhibition of Rac-dependent Pak1 phosphorylation and lamellipodia formation and in impairment of trafficking of plexinB1 to the membrane. None of the three characterised mutations affect PDZRhoGEF binding, RhoA activity, the interaction of plexinB1with the oncogenes ErbB2 or c-Met or ErbB2 phosphorylation. The mutations have the net effect of increasing cell motility by blocking plexinB1-mediated inhibition of Rac while enhancing the interaction with RhoD, an anti-migratory factor.PlexinB1 mutations block plexinB1-mediated signalling pathways that inhibit cell motility.Semaphorins are a group of 20 or more secreted or membrane bound proteins [1] that act as chemotactic cues for cells expressing their transmembrane receptors plexins [2]. Semaphorins affect cell behaviour in diverse ways, regulating cell motility [3], invasive capacity [4], adhesion [5] and cell and axon growth cone collapse [6]. Semaphorins consequently have a function in many physiological processes including angiogenesis [7], cell migration [8,9], immune regulation [10] and organogenesis, affecting nervous system [11,12], lung [13], kidney [14] and cardiovascular development [15,16] and epithelial-mesenchymal interactions [14]. The response of a cell to semaphorin stimulation depends on the type of responding cell and particular semaphorins can generate opposite reactions depending on cell type [17]. The transmembrane semaphorin receptors, plexins, either bind semaphorins directly, or in the case of most class 3 semaphorins, to a complex of neuropilins and plexins [2,18]. Semaphorin 4D (Sema4D) binds directly to its receptor, plexinB1 [2].Semaphorin/plexin signalling results in activation of receptor tyrosine kinases and modulation of the actin cytoskeleton via regulation of several specific small RhoGTPases. PlexinB1 binds to RacGTP [19,20], sequestering it from its downstream effectors,