Neurophysiological process Receptor-mediated axon growth repulsion
Receptor-mediated axon growth repulsion Ephrin-A proteins which are anchored in the plasma membrane through attachmentof glycosylphosphatidylinositol ( GPI ) , are the ligands forEphrin-A receptors, which belong to the membrane family of receptor tyrosinekinases . In the absence of Ephrin-A stimulation, Ephrin-A receptors are shown totarget Ephexin exchange factor to the plasma membrane. Ephrin-A stimulationof Ephrin-A receptors activates exchange factors Ephexin , VAV-2  and Tiam 1. Src -family tyrosine kinases c-Src and Fyn are recruitedto Ephrin-A receptors after Ephrin-A stimulation . Inresponse to Ephrin-A signaling Ephexin becomes phosphorylated byc-Src  and this phosphorylation enhances its activity toward Rashomolog gene family, member A ( RhoA ) . VAV-2 is rapidlyphosphorylated by c-Src upon stimulation by Ephrin-A  andactivates RhoA . Ephrin-A receptors have also been shown to signal through the Ras-related C3botulinum toxin substrate 1 ( Rac1 ) exchange factors Tiam1  and VAV-2  to promote neurite outgrowth. In response to Ephrin-A1 stimulation, Ras-related protein Rap-1A isactivated  and can regulate MAPK signaling cascade by reducingc-Raf-1 activation  or by stimulation of B-Raf kinase , . When Ephrin-A receptors are activated, phosphorylation of Ephexinpromotes its GTPase activity toward RhoA. RhoA downstream effectorRho-associated kinase ROCK directly phosphorylates LIM-kinases LIMK1 andLIMK2, which in turn phosphorylates actin-depolymerizing factor destrinand actin-associated protein cofilin. Activity of LIMK1 is also regulatedby p21-activated kinase 1 ( PAK1 ) . Cofilin anddestrin both exhibit actin -depolymerizing activity followed byreorganization of the actin cytoskeleton , . The F-actin-binding protein cortactin is an important regulator of cytoskeletaldynamics, and a prominent target of various tyrosine kinases ( c-Src, Fyn, Fer ) , . Tyrosine phosphorylation ofcortactin has been suggested to reduce its F-actin cross-linking capability . The semaphorins family of secreted or membrane-bound proteins was identifiedoriginally as axonal guidance factors functioning during neuronal development. The class4 semaphorin Semaphorin 4D utilizes Plexin B1 (transmembrane protein) asreceptor.  Plexin B1 directly interacts with exchange factorsPDZ-RhoGEF and LARG to regulate RhoA and the growth cone morphology. Rho6 is a member of Rho family GTPases. It is activated by adaptor proteinGrb7 and directly interacts with the cytoplasmic domain of Plexin B1 inresponse to Semaphorin 4D. Rho6 promotes the interaction between PlexinB1 and PDZ-RhoGEF and thereby potentiates the PDZ-RhoGEF -inducedRhoA activation . PAK1 promotes activation of actin polymerization by phosphorylation ofArp2/3 (complex of actin-related proteins) . c-Raf-1kinase, a member of the MAPK pathway, is also phosphorylated and activated by PAK1. Inhibition of Pak1 by Plexin B1 is believed to causesuppression of membrane protrusions, thus supporting the cell repulsion response.Furthermore, active Rac1 was shown to promote cell surface localization ofPlexin B1 thus enhancing Semaphorin 4D binding to the receptor. Thus,Rac1 and Plexin B1 signaling appears to be bidirectional: Rac-1modulates Plexin B1 activity, and Plexin B1 modulates Rac-1 function. Another semaphorin, Semaphorin 3A, binds to Neuropilin-1/ PlexinA1 complex and induces repulsive responses . The active form ofRac1 directly binds to Plexin-A1. A ctivated Rac1 mediatesendocytosis of the growth cone plasma membranes and reorganization of F-actin inneurons . Endocytosis of plasma membranes is supposed to be an importantstep for growth cone collapse. c-Fes tyrosine kinase also is implicated in Semaphorin 3A -inducedcollapse . c-Fes directly binds to the cytoplasmic region ofPlexin A1. In the resting state, neuropilin-1 associates withPlexin-A1 and blocks the binding of c-Fes to Plexin A1.Semaphorin 3A binding to Neuropilin-1 permits c-Fes to associatewith and phosphorylate Plexin A1. This tyrosine phosphorylation stimulatesrepulsive action in the receptor. c-Fes also phosphorylates collapsin response mediator protein CRMP2. Fyn, a member of src-family of tyrosine kinases, associates with PlexinA2 in response to Semaphorin 3A and phosphorylates s erine/threonine kinaseCDK5.  Activated CDK5 phosphorylates CRMP2 . ROCK2 kinase also has been shown to phosphorylate CRMP2 . CRMP2 binds to tubulin heterodimers to promote microtubule assembly that isimportant for axonal growth and branching . Phosphorylation ofCRMP2 reduces its tubulin-heterodimer binding and the promotion of microtubuleassembly. CDK5 also phosphorylates the microtubule-associated protein Tau,thereby reduces its ability to induce tubulin microtubule formation .