Cytoskeleton remodeling Reverse signaling by ephrin B
Reverse signaling by Ephrin B Ephrin receptors and Ephrins are both membrane bound, and followingtheir interaction and clustering, each can transduce signals that regulate cell responses. Ephrin receptors activate reverse signaling through their Ephrin ligands. Ephrin-B receptors induce Ephrin-B tyrosine phosphorylation. Src familykinases are responsible for Ephrin-B phosphorylation, but this activation istransient. At later time points Ephrin-B ligands recruit phosphotyrosinePhosphatase protein-tyrosine phosphatase PTPL1 ( FAP-1 ) to the membrane andbecome dephosphorylated. This is suggested the presence of a switch mechanism that allowsEphrin-B ligands to shift from fast phosphotyrosine/Src-dependent signaling todelayed signaling . Tyrosine phosphorylation of Ephrin-B results in binding of the NCK adaptorprotein 2 ( Grb4), which links Ephrin-B to a vast signaling network thatmodifies cell morphology through reorganization of Actin cytoskeleton . Grb4 could associate with a number of signaling molecules. It can bind toG-factor Son of sevenless homolog ( SOS ) , followed by activationof transforming protein v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS), protein kinase V-raf-1 murine leukemia viral oncogene homolog ( c-Raf ) andMAPK-cascade signaling. Grb4 binding to p21 protein-activated kinase 1 ( PAK1 ) and to the WAS/WASL interacting protein family, member 2 ( WIRE ) with subsequentactivation of Wiskott-Aldrich syndrome protein ( N-WASP ) promotes complex of ARPactin-related proteins homologs ( Arp2/3 ) activation and Actinpolymerization . Activity of the N-WASP is also facilitated byanother WASP interacting protein WAS/WASL interacting protein family member 1 (WaspIP ) . Binding of Grb4 to LIM and senescent cell antigen-like domains 1 (PINCH) and to Axin regulates Beta-catenin activity and Wingless-typeMMTV integration site family ( WNT ) proteins signaling. PINCH is a binding protein for Integrin-linked kinase ( ILK ) , which phosphorylates downstream glycogen synthase kinase 3 ( GSK3 ) anddown-regulates its activity . PINCH-2, another member of thePINCH protein family, forms a complex with ILK and significantly inhibitsthe PINCH/ ILK interaction . Axin forms a complex with Glycogen synthase kinase 3 beta ( GSK3 beta )and Beta-catenin and promotes GSK3 beta -dependent phosphorylation ofBeta-catenin, thereby stimulating degradation of Beta-catenin. GSK3beta in turn phosphorylates Axin in the complex, which is important for theregulation of its stability . GSK3 beta also phosphorylates neuronal microtubule-associated proteinMicrotubule-associated protein tau ( Tau (MAPT) ) . Thisphosphorylation does not alter Tau 's ability to bind to Tubulin inmicrotubules but appears to be required for the maintenance of the anterograde organelletransport in differentiated cells . Paxillin is a focal adhesion-associated protein that also could bind to bothTubulin alpha and gamma of the cellular microtubule cytoskeleton . Activation of Ephrin-B1 leads to phosphorylation of focal adhesion kinase(FAK1 ) by V-src sarcoma viral oncogene homolog ( c-Src), which increasesFAK1 activity, and leads to redistribution of the FAK1 -binding proteinPaxillin and disassembly of focal adhesions . These signaling pathways lead to rounding of cell morphology and cell repulsion. A mechanism that may serve to turn off phosphorylation-dependent Ephrin-Breverse signals involves delayed recruitment of the FAP-1, which thendephosphorylates the cytoplasmic domain of Ephrin-B . Ephrin-B ligands, even after dephosphorylating, can initiate reverse signalingthrough binding to the Regulator of G-protein signaling 3 ( RGS3 ), whichcatalyzes hydrolysis of GTP to GDP in the Guanine nucleotide binding protein alphainhibiting activity polypeptide 1 ( G-protein alpha-i )-subunits, therebyinhibiting their activity. RGS3 might inhibit Stromal cell derived factor 1 (SDF1 )-mediated cerebellar granule cell chemotaxis through Chemokine receptor 4 (CXCR4 ) G-protein -coupled chemokine receptor . Thissignaling mechanism may have broad implications for cell migratory behavior in differentsystems .