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[1].
Ephrin receptors activate reverse signaling through their Ephrin ligands[2].
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 [3].
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 [4].
Grb4 could associate with a number of signaling molecules. It can bind toG-factor Son of sevenless homolog ( SOS ) [5], 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 ) [4]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 [6]. Activity of the N-WASP is also facilitated byanother WASP interacting protein WAS/WASL interacting protein family member 1 (WaspIP ) [7].
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 ) [8], which phosphorylates downstream glycogen synthase kinase 3 ( GSK3 ) anddown-regulates its activity [9]. PINCH-2, another member of thePINCH protein family, forms a complex with ILK and significantly inhibitsthe PINCH/ ILK interaction [10].
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 [11].
GSK3 beta also phosphorylates neuronal microtubule-associated proteinMicrotubule-associated protein tau ( Tau (MAPT) ) [12]. 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 [13].
Paxillin is a focal adhesion-associated protein that also could bind to bothTubulin alpha and gamma of the cellular microtubule cytoskeleton [14].
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 [4].
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 [3].
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 [15]. Thissignaling mechanism may have broad implications for cell migratory behavior in differentsystems [2].
Map Key
