Cytoskeleton remodeling - Reverse signaling by ephrin B

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Reverse signaling by Ephrin B

Ephrin receptors and Ephrins are both membrane bound, and following their 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 family kinases are responsible for Ephrin-B phosphorylation, but this activation is transient. At later time points Ephrin-B ligands recruit phosphotyrosine Phosphatase protein-tyrosine phosphatase PTPL1 (FAP-1) to the membrane and become dephosphorylated. This is suggested the presence of a switch mechanism that allows Ephrin-B ligands to shift from fast phosphotyrosine/Src-dependent signaling to delayed signaling [3].

Tyrosine phosphorylation of Ephrin-B results in binding of the NCK adaptor protein 2 (Grb4), which links Ephrin-B to a vast signaling network that modifies cell morphology through reorganization of Actin cytoskeleton [4].

Grb4 could associate with a number of signaling molecules. It can bind to G-factor Son of sevenless homolog (SOS) [5], followed by activation of 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) and MAPK-cascade signaling.

Grb4 binding to p21 protein-activated kinase 1 (PAK1) [4] and to the WAS/WASL interacting protein family, member 2 (WIRE) with subsequent activation of Wiskott-Aldrich syndrome protein (N-WASP) promotes complex of ARP actin-related proteins homologs (Arp2/3) activation and Actin polymerization [6]. Activity of the N-WASP is also facilitated by another 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-type MMTV 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) and down-regulates its activity [9]. PINCH-2, another member of the PINCH protein family, forms a complex with ILK and significantly inhibits the 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 of Beta-catenin, thereby stimulating degradation of Beta-catenin. GSK3 beta in turn phosphorylates Axin in the complex, which is important for the regulation of its stability [11].

GSK3 beta also phosphorylates neuronal microtubule-associated protein Microtubule-associated protein tau (Tau (MAPT)) [12]. This phosphorylation does not alter Tau's ability to bind to Tubulin in microtubules but appears to be required for the maintenance of the anterograde organelle transport in differentiated cells [13].

Paxillin is a focal adhesion-associated protein that also could bind to both Tubulin 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 increases FAK1 activity, and leads to redistribution of the FAK1-binding protein Paxillin 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-B reverse signals involves delayed recruitment of the FAP-1, which then dephosphorylates the cytoplasmic domain of Ephrin-B [3].

Ephrin-B ligands, even after dephosphorylating, can initiate reverse signaling through binding to the Regulator of G-protein signaling 3 (RGS3), which catalyzes hydrolysis of GTP to GDP in the Guanine nucleotide binding protein alpha inhibiting activity polypeptide 1 (G-protein alpha-i)-subunits, thereby inhibiting 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]. This signaling mechanism may have broad implications for cell migratory behavior in different systems [2].

References:

  1. Poliakov A, Cotrina M, Wilkinson DG
    Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Developmental cell 2004 Oct;7(4):465-80
  2. Murai KK, Pasquale EB
    'Eph'ective signaling: forward, reverse and crosstalk. Journal of cell science 2003 Jul 15;116(Pt 14):2823-32
  3. Palmer A, Zimmer M, Erdmann KS, Eulenburg V, Porthin A, Heumann R, Deutsch U, Klein R
    EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Molecular cell 2002 Apr;9(4):725-37
  4. Cowan CA, Henkemeyer M
    The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 2001 Sep 13;413(6852):174-9
  5. Braverman LE, Quilliam LA
    Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck. The Journal of biological chemistry 1999 Feb 26;274(9):5542-9
  6. Irie F, Yamaguchi Y
    EPHB receptor signaling in dendritic spine development. Frontiers in bioscience : a journal and virtual library 2004 May 1;9:1365-73
  7. Aspenstrom P
    The WASP-binding protein WIRE has a role in the regulation of the actin filament system downstream of the platelet-derived growth factor receptor. Experimental cell research 2002 Sep 10;279(1):21-33
  8. Tu Y, Li F, Goicoechea S, Wu C
    The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. Molecular and cellular biology 1999 Mar;19(3):2425-34
  9. Wu C
    Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction. Journal of cell science 1999 Dec;112 ( Pt 24):4485-9
  10. Zhang Y, Chen K, Guo L, Wu C
    Characterization of PINCH-2, a new focal adhesion protein that regulates the PINCH-1-ILK interaction, cell spreading, and migration. The Journal of biological chemistry 2002 Oct 11;277(41):38328-38
  11. Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A
    Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. The Journal of biological chemistry 1999 Apr 16;274(16):10681-4
  12. Ishii T, Furuoka H, Muroi Y, Nishimura M
    Inactivation of integrin-linked kinase induces aberrant tau phosphorylation via sustained activation of glycogen synthase kinase 3beta in N1E-115 neuroblastoma cells. The Journal of biological chemistry 2003 Jul 18;278(29):26970-5
  13. Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I
    Role of tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport. Journal of cell science 2004 Apr 1;117(Pt 9):1653-63
  14. Herreros L, Rodriguez-Fernandez JL, Brown MC, Alonso-Lebrero JL, Caba?as C, Sanchez-Madrid F, Longo N, Turner CE, Sanchez-Mateos P
    Paxillin localizes to the lymphocyte microtubule organizing center and associates with the microtubule cytoskeleton. The Journal of biological chemistry 2000 Aug 25;275(34):26436-40
  15. Lu Q, Sun EE, Klein RS, Flanagan JG
    Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 2001 Apr 6;105(1):69-79

  1. Poliakov A, Cotrina M, Wilkinson DG
    Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Developmental cell 2004 Oct;7(4):465-80
  2. Murai KK, Pasquale EB
    'Eph'ective signaling: forward, reverse and crosstalk. Journal of cell science 2003 Jul 15;116(Pt 14):2823-32
  3. Palmer A, Zimmer M, Erdmann KS, Eulenburg V, Porthin A, Heumann R, Deutsch U, Klein R
    EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Molecular cell 2002 Apr;9(4):725-37
  4. Cowan CA, Henkemeyer M
    The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 2001 Sep 13;413(6852):174-9
  5. Braverman LE, Quilliam LA
    Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck. The Journal of biological chemistry 1999 Feb 26;274(9):5542-9
  6. Irie F, Yamaguchi Y
    EPHB receptor signaling in dendritic spine development. Frontiers in bioscience : a journal and virtual library 2004 May 1;9:1365-73
  7. Aspenstrom P
    The WASP-binding protein WIRE has a role in the regulation of the actin filament system downstream of the platelet-derived growth factor receptor. Experimental cell research 2002 Sep 10;279(1):21-33
  8. Tu Y, Li F, Goicoechea S, Wu C
    The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. Molecular and cellular biology 1999 Mar;19(3):2425-34
  9. Wu C
    Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction. Journal of cell science 1999 Dec;112 ( Pt 24):4485-9
  10. Zhang Y, Chen K, Guo L, Wu C
    Characterization of PINCH-2, a new focal adhesion protein that regulates the PINCH-1-ILK interaction, cell spreading, and migration. The Journal of biological chemistry 2002 Oct 11;277(41):38328-38
  11. Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A
    Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. The Journal of biological chemistry 1999 Apr 16;274(16):10681-4
  12. Ishii T, Furuoka H, Muroi Y, Nishimura M
    Inactivation of integrin-linked kinase induces aberrant tau phosphorylation via sustained activation of glycogen synthase kinase 3beta in N1E-115 neuroblastoma cells. The Journal of biological chemistry 2003 Jul 18;278(29):26970-5
  13. Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I
    Role of tau phosphorylation by glycogen synthase kinase-3beta in the regulation of organelle transport. Journal of cell science 2004 Apr 1;117(Pt 9):1653-63
  14. Herreros L, Rodriguez-Fernandez JL, Brown MC, Alonso-Lebrero JL, Caba?as C, Sanchez-Madrid F, Longo N, Turner CE, Sanchez-Mateos P
    Paxillin localizes to the lymphocyte microtubule organizing center and associates with the microtubule cytoskeleton. The Journal of biological chemistry 2000 Aug 25;275(34):26436-40
  15. Lu Q, Sun EE, Klein RS, Flanagan JG
    Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 2001 Apr 6;105(1):69-79

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