Pathway Map Details

Development_MAG-dependent inhibition of neurite outgrowth



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Destrin, MLCP (cat), NGF, ganglioside GD1a, TrkB, RhoGDI alpha, RhoA, TrkC, Reticulon 4, gamma-Secretase complex, p200RhoGAP, OMgp, NGFR (CTF), NGFR(TNFRSF16), MRLC, LIMK1, Cofilin, Actin cytoskeletal, MAG, ADAM17, MLCP (reg), Lingo1, Myosin II, NGFR = NGFR (CTF), NT-4/5, MELC, NGFR (CTF) = NGFR (ICD), RASGRF1, BDNF, MyHC, RTN4R, NGFR (ICD), TrkA, NT-3, N-acetyl- neuraminic acid, ganglioside GT1b, ROCK

Description:

MAG-dependent inhibition of neurite outgrowth

Neurotrophins are key regulators of the fate and shape of neuronal cells. They act as guidance cues for growth cones by remodeling actin cytoskeleton. Neurotrophins ( NGF, BDNF, NT-3 and NT-4/5 ) bind to two structurally unrelated receptors, tyrosine kinase Trk receptors ( TrkA, TrkB and TrkC ), and Tumor necrosis factor receptor superfamily member 16 ( NGFR(TNFRSF16) ). Trk receptors and NGFR(TNFRSF16) are closely associated in cellular membranes.

Actin dynamics is controlled by Rho GTPases, which, in turn, are regulated by opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GAP p200RhoGAP, which is constitutively associated with TrkA, inhibits RhoA activity, which leads to neurite outgrowth [1], [2]. GEF RASGRF1, that is phosphorylated and activated by TrkA, TrkB, and TrkC, stimulates RhoA activity, followed by inhibition of neurite outgrowth [3]. RhoA downstream effector ROCK kinases directly phosphorylate kinase LIMK1, which, in turn, phosphorylates Cofilin that exhibits actin -depolymerizing activity [4], [5]. Activated ROCK kinases subsequently inactivate myosin light chain phosphatase ( MLCP ) by phosphorylation [6], which attenuates myosin light chains ( MELC ) and myosin regulatory light chains ( MRLC ) phosphorylation [7] and formation of actomyosin fibers.

Myelin-associated protein ( MAG or siglec-4) is a lectin that binds to sialylated glycoconjugates (via N-acetyl-neuraminic acid ) and mediates certain myelin-neuron cell-cell interactions. MAG, expressed by oligodendrocytes and Schwann cells in the nervous system, is important for maintaining the integrity of the myelin sheath.

Binding of MAG to the NGFR(TNFRSF16), as well as its binding to N-acetyl-neuraminic acid, gangliosides GD1a and GT1b on neuronal cells results in activation of NGFR(TNFRSF16), that is associated with ganglioside GT1b [8], [9]. MAG binding to NGFR(TNFRSF16) promotes ADAM metallopeptidase domain 17 ( ADAM17 ) - mediated ectodomain shedding that generates NGFR(TNFRSF16) C-terminal fragment NGFR (CTF). Gamma-Secretase complex cleaves NGFR (CTF) and liberates NGFR(TNFRSF16) intracytoplasmic domain NGFR (ICD) [10], [11]. NGFR (ICD) sequesters Rho GDP dissociation inhibitor (GDI) alpha ( RhoGDI alpha ) that leads to RhoA activation [12], [13], [14]. These interactions induce RhoA, stimulation of ROCK kinases, actomyosin fibers formation, and inhibition of neurite outgrowth.

MAG can also bind to Nogo receptor ( RTN4R ) in a sialic-acid-independent manner. This interaction is functionally important for MAG -dependent neurite inhibition. RTN4R plays central role in mediating growth-inhibitory activities of myelin-derived proteins. Inhibitory protein Reticulon 4 and oligodendrocyte myelin glycoprotein ( OMgp ) bind to RTN4R to inhibit axonal outgrowth [15]. Lingo1, a nervous system-specific transmembrane protein, binds to RTN4R and NGFR(TNFRSF16), which is an additional functional component of RTN4R/ NGFR(TNFRSF16) signaling complex [16]. Thus, MAG -dependent inhibition of neurite outgrowth depends on the complex molecular interaction between MAG, ganglioside GT1b, NGFR(TNFRSF16), Lingo1 and RTN4R [17].

References:

  1. Nakamura T, Komiya M, Sone K, Hirose E, Gotoh N, Morii H, Ohta Y, Mori N
    Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules. Molecular and cellular biology 2002 Dec;22(24):8721-34
  2. Moon SY, Zang H, Zheng Y
    Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP. The Journal of biological chemistry 2003 Feb 7;278(6):4151-9
  3. Robinson KN, Manto K, Buchsbaum RJ, MacDonald JI, Meakin SO
    Neurotrophin-dependent tyrosine phosphorylation of Ras guanine-releasing factor 1 and associated neurite outgrowth is dependent on the HIKE domain of TrkA. The Journal of biological chemistry 2005 Jan 7;280(1):225-35
  4. Wilson JG
    Reproduction and teratogenesis: current methods and suggested improvements. Journal - Association of Official Analytical Chemists. 1975 Jul;58(4):657-67
  5. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S
    Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999 Aug 6;285(5429):895-8
  6. Riento K, Ridley AJ
    Rocks: multifunctional kinases in cell behaviour. Nature reviews. Molecular cell biology. 2003 Jun;4(6):446-56
  7. Pfitzer G
    Invited review: regulation of myosin phosphorylation in smooth muscle. Journal of applied physiology (Bethesda, Md. : 1985) 2001 Jul;91(1):497-503
  8. Vinson M, Strijbos PJ, Rowles A, Facci L, Moore SE, Simmons DL, Walsh FS
    Myelin-associated glycoprotein interacts with ganglioside GT1b. A mechanism for neurite outgrowth inhibition. The Journal of biological chemistry 2001 Jun 8;276(23):20280-5
  9. Vyas AA, Patel HV, Fromholt SE, Heffer-Lauc M, Vyas KA, Dang J, Schachner M, Schnaar RL
    Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proceedings of the National Academy of Sciences of the United States of America 2002 Jun 11;99(12):8412-7
  10. Zampieri N, Xu CF, Neubert TA, Chao MV
    Cleavage of p75 neurotrophin receptor by alpha-secretase and gamma-secretase requires specific receptor domains. The Journal of biological chemistry 2005 Apr 15;280(15):14563-71
  11. Bronfman FC
    Metalloproteases and gamma-secretase: new membrane partners regulating p75 neurotrophin receptor signaling? Journal of neurochemistry 2007 Nov;103 Suppl 1:91-100
  12. Yamashita T, Higuchi H, Tohyama M
    The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. The Journal of cell biology 2002 May 13;157(4):565-70
  13. Yamashita T, Tohyama M
    The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nature neuroscience 2003 May;6(5):461-7
  14. Domeniconi M, Zampieri N, Spencer T, Hilaire M, Mellado W, Chao MV, Filbin MT
    MAG induces regulated intramembrane proteolysis of the p75 neurotrophin receptor to inhibit neurite outgrowth. Neuron 2005 Jun 16;46(6):849-55
  15. Schimmele B, Pluckthun A
    Identification of a functional epitope of the Nogo receptor by a combinatorial approach using ribosome display. Journal of molecular biology 2005 Sep 9;352(1):229-41
  16. Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB
    LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature neuroscience 2004 Mar;7(3):221-8
  17. Crocker PR
    Siglecs: sialic-acid-binding immunoglobulin-like lectins in cell-cell interactions and signalling. Current opinion in structural biology 2002 Oct;12(5):609-15