FARP2 triggers signals for Sema3A-mediated axonal repulsion

Abstract

Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit. How the signals downstream of plexin-A1 are triggered upon Sema3A stimulation, however, is unknown. Here we show that, in the presence of neuropilin-1, the FERM domain-containing guanine nucleotide exchange factor (GEF) FARP2 associates directly with plexin-A1. Sema3A binding to neuropilin-1 induces the dissociation of FARP2 from plexin-A1, resulting in activation of FARP2's Rac GEF activity, Rnd1 recruitment to plexin-A1, and downregulation of R-Ras. Simultaneously, the FERM domain of FARP2 sequesters phosphatidylinositol phosphate kinase type I isoform PIPKIgamma661 from talin, thereby inhibiting its kinase activity. These activities are required for Sema3A-mediated repulsion of outgrowing axons and suppression of neuronal adhesion. We therefore conclude that FARP2 is a key molecule involved in the response of neuronal growth cones to class-3 semaphorins.

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…In addition, recent reports revealed that PI(4,5)P 2 acts as a second messenger and controls focal adhesion dynamics and actin cytoskeleton [57], both of which are critical for cell migration. In neuronal cells, inhibition of another isoform of PIP5K, PIPKIγ661, is required for Sema3A-induced axonal repulsion and growth cone collapse [42]. These data suggest that semaphorins may commonly utilize phospholipid-regulated signaling Figure 2 Anti-angiogenic signaling by Sema3E-plexin D1 in endothelial cells.…”

“…The molecular mechanisms by which Sema3A regulates integrins are not fully understood. From the studies in neuronal cells, it is likely that activation of plexin-A1 by Sema3A induces the intrinsic R-Ras GAP activity of Plexin-A1, thus resulting in R-Ras inhibition [16,42]. As R-Ras is known to sustain integrin activation, the inactivation of R-Ras by plexin-A1 may lead to the inactivation of integrins, thereby inhibiting integrinmediated cell adhesion.…”

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.…”

Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration

“…Of particular interest is the recognition that the plexin intracellular region exhibits sequence similarity to Ras GTPase-activating proteins (Ras GAPs), representing the first example of a transmembrane receptor containing a GAP domain (6,7). R-Ras, a homologue of Ras involved in regulating cell adhesion and neurite outgrowth, is a substrate of the plexin GAP (8,9). Conversion of R-Ras into the GDP-bound inactive form by the plexin GAP leads to decreased activity of integrin and loss of cell adhesion, contributing to repulsive axon guidance.…”