Plexin-B1 Directly Interacts with PDZ-RhoGEF/LARG to Regulate RhoA and Growth Cone Morphology

Abstract

Plexins are widely expressed transmembrane proteins that, in the nervous system, mediate repulsive signals of semaphorins. However, the molecular nature of plexin-mediated signal transduction remains poorly understood. Here, we demonstrate that plexin-B family members associate through their C termini with the Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG. Activation of plexin-B1 by semaphorin 4D regulates PDZ-RhoGEF/LARG activity leading to RhoA activation. In addition, a dominant-negative form of PDZ-RhoGEF blocks semaphorin 4D-induced growth cone collapse in primary hippocampal neurons. Our study indicates that the interaction of mammalian plexin-B family members with the multidomain proteins PDZ-RhoGEF and LARG represents an essential molecular link between plexin-B and localized, Rho-mediated downstream signaling events which underly various plexin-mediated cellular phenomena including axonal growth cone collapse.

Regulation of immune cell responses by semaphorins and their receptors

“…In the nervous system, semaphorin-plexin signaling has been shown to mediate diverse neural functions by regulating GTPase activities and cytoplasmic/receptor-type protein kinases. 11,31,32 These plexin-mediated signals are involved in integrin-mediated attachment, 15,33,34 actomyosin contraction [35][36][37][38] and microtubule destabilization. [39][40][41] In addition, plexins can associate with different coreceptors in distinct tissues to allow semaphorins to exert pleiotropic functions.…”

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…These results support a role of ERK activation in the regulation of iNOS production by Sema4D in microglia. It has been reported that plexin-B1, through association with PDZ-r guanine nucleotide exchange factors and leukemia-associated RhoGEF, is involved in activation of RhoA in response to Sema4D (17,36) and that ERK1/2 can be activated via plexin-B1 in neural cells and endothelial cells (34,35). In this context, it is plausible that plexin-B1 regulates ERK1/2 signaling pathways in concert with CD40 signals.…”

“…We previously demonstrated the activation of B cells and DCs through the Sema4D-CD72 interactions (15,16); Sema4D-deficient mice display severe impairments in activation of B cells and DCs, resulting in impaired Ab production and Agspecific T cell priming (13,16). In the nervous system, Sema4D participates in axon guidance by regulating activities of RhoA through PDZ-r guanine nucleotide exchange factors and leukemiaassociated RhoGEF (17). In addition, plexin-B1 has been shown to mediate repellent signals in hypocampal neurons by directly binding Rnd1 and downregulating R-ras activity in response to Sema4D (18).…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…In transfected cells, Sema4D binds to plexin-B1 leading to the small GTPases Rac1 and RhoA signaling pathway. 59,60 Plexin-B1, -B2 and -B3 can also form receptor complexes with Met and Ron. 61,62 It was shown that SEMA4D fixation on plexin-B1 can trigger invasive response of NIH3T3 cells in vitro by activating MET and Ron.…”