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PMID: 15014045 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Role of Unc51.1 and its binding partners in CNS axon outgrowth.

Genes & development ·Vol. 18 ·No. 5 ·2004-03-01 ·Pages 541-58

Tomoda T, Kim JH, Zhan C, Hatten ME

Abstract

Previous studies showed that the serine/threonine kinase Unc51.1 is one of the earliest genes in neuronal differentiation and is required for granule cell axon formation. To examine the mechanism of Unc51.1 regulation of axon extension, we have identified two direct binding partners. The first, SynGAP, a negative regulator of Ras, is expressed within axons and growth cones of developing granule cells. Overexpression of SynGAP blocks neurite outgrowth by a mechanism that involves Ras-like GTPase cascade. The second binding partner is a PDZ domain-containing scaffolding protein, Syntenin, that binds Rab5 GTPase, the activity of which is attenuated by SynGAP. Thus, our results demonstrate that the Unc51.1-containing protein complex governs axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.

MeSH Terms
Animals Autophagy-Related Protein-1 Homolog Axons/enzymology,ultrastructure Carrier Proteins/metabolism,physiology Cell Differentiation Central Nervous System/embryology,growth & development Embryonic and Fetal Development/physiology Endocytosis GTPase-Activating Proteins/metabolism,physiology Mice Nerve Tissue Proteins/metabolism,physiology Neurons/cytology,enzymology,ultrastructure Protein Binding Protein Serine-Threonine Kinases/metabolism,physiology Receptors, Cell Surface/metabolism,physiology Syntenins rab5 GTP-Binding Proteins/metabolism ras GTPase-Activating Proteins/metabolism,physiology ras Proteins/metabolism
Chemicals
Carrier Proteins GTPase-Activating Proteins Nerve Tissue Proteins Receptors, Cell Surface Sdcbp protein, mouse Syngap1 protein, mouse Syntenins ras GTPase-Activating Proteins Ulk2 protein, mouse Autophagy-Related Protein-1 Homolog Protein Serine-Threonine Kinases Ulk1 protein, mouse rab5 GTP-Binding Proteins ras Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Tomoda Toshifumi
Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York 10021-6399, USA.
Kim Jee Hae
Zhan Caixin
Hatten Mary E
References (59)
59 references, click to expand
  1. Interaction of the Unc-51-like kinase and microtubule-associated protein light chain 3 related proteins in the brain: possible role of vesicular transport in axonal elongation.
    Brain Res Mol Brain Res. 2000 Dec 28;85(1-2):1-12 PMID: 11146101
  2. Identification of syntenin as a protein of the apical early endocytic compartment in Madin-Darby canine kidney cells.
    J Biol Chem. 1999 Sep 10;274(37):26233-9 PMID: 10473577
  3. RUN domains: a new family of domains involved in Ras-like GTPase signaling.
    Trends Biochem Sci. 2001 Feb;26(2):79-83 PMID: 11166556
  4. Mammalian MAP kinase signalling cascades.
    Nature. 2001 Mar 1;410(6824):37-40 PMID: 11242034
  5. Rab proteins as membrane organizers.
    Nat Rev Mol Cell Biol. 2001 Feb;2(2):107-17 PMID: 11252952
  6. Molecular dissection of autophagy: two ubiquitin-like systems.
    Nat Rev Mol Cell Biol. 2001 Mar;2(3):211-6 PMID: 11265251
  7. The neural cell recognition molecule neurofascin interacts with syntenin-1 but not with syntenin-2, both of which reveal self-associating activity.
    J Biol Chem. 2001 Apr 6;276(14):10646-54 PMID: 11152476
  8. Characterization of a novel synGAP isoform, synGAP-beta.
    J Biol Chem. 2001 Jun 15;276(24):21417-24 PMID: 11278737
  9. A mouse serine/threonine kinase homologous to C. elegans UNC51 functions in parallel fiber formation of cerebellar granule neurons.
    Neuron. 1999 Dec;24(4):833-46 PMID: 10624947
  10. Rab GTPases coordinate endocytosis.
    J Cell Sci. 2000 Jan;113 Pt 2:183-92 PMID: 10633070
  11. Ras protein signalling.
    Semin Immunol. 2000 Feb;12(1):63-73 PMID: 10723799
  12. GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28.
    EMBO J. 2000 Apr 3;19(7):1494-504 PMID: 10747018
  13. Molecular dissection of TrkA signal transduction pathways mediating differentiation in human neuroblastoma cells.
    Oncogene. 2000 Apr 13;19(16):2043-51 PMID: 10803465
  14. Recycling of the cell adhesion molecule L1 in axonal growth cones.
    J Neurosci. 2000 May 15;20(10):3676-86 PMID: 10804209
  15. Tor-mediated induction of autophagy via an Apg1 protein kinase complex.
    J Cell Biol. 2000 Sep 18;150(6):1507-13 PMID: 10995454
  16. Mechanisms of synaptic vesicle exocytosis.
    Annu Rev Cell Dev Biol. 2000;16:19-49 PMID: 11031229
  17. Autophagy as a regulated pathway of cellular degradation.
    Science. 2000 Dec 1;290(5497):1717-21 PMID: 11099404
  18. Mechanism and role of PDZ domains in signaling complex assembly.
    J Cell Sci. 2001 Sep;114(Pt 18):3219-31 PMID: 11591811
  19. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1.
    Dev Cell. 2001 Jul;1(1):73-82 PMID: 11703925
  20. Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.
    Nature. 2002 May 23;417(6887):443-7 PMID: 11986622
  21. Commissureless is required both in commissural neurones and midline cells for axon guidance across the midline.
    Development. 2002 Jun;129(12):2947-56 PMID: 12050141
  22. Rac1-mediated endocytosis during ephrin-A2- and semaphorin 3A-induced growth cone collapse.
    J Neurosci. 2002 Jul 15;22(14):6019-28 PMID: 12122063
  23. Comm sorts robo to control axon guidance at the Drosophila midline.
    Cell. 2002 Aug 23;110(4):415-27 PMID: 12202032
  24. Control of semaphorin signaling.
    Curr Opin Neurobiol. 2002 Oct;12(5):532-41 PMID: 12367632
  25. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor.
    J Neurosci. 2002 Nov 15;22(22):9721-32 PMID: 12427827
  26. Molecular mechanisms of axon guidance.
    Science. 2002 Dec 6;298(5600):1959-64 PMID: 12471249
  27. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity.
    J Neurosci. 2003 Feb 15;23(4):1119-24 PMID: 12598599
  28. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.
    Neuron. 2003 Feb 20;37(4):625-38 PMID: 12597860
  29. An essential role of Rab5 in uniformity of synaptic vesicle size.
    J Cell Sci. 2003 Sep 1;116(Pt 17):3583-90 PMID: 12876219
  30. EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion.
    Nat Cell Biol. 2003 Oct;5(10):869-78 PMID: 12973358
  31. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
    Nature. 1970 Aug 15;227(5259):680-5 PMID: 5432063
  32. Relationship between peroxisomes and endoplasmic reticulum investigated by combined catalase and glucose-6-phosphatase cytochemistry.
    J Histochem Cytochem. 1981 Nov;29(11):1263-72 PMID: 6274950
  33. Neuronal regulation of astroglial morphology and proliferation in vitro.
    J Cell Biol. 1985 Feb;100(2):384-96 PMID: 3881455
  34. Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes.
    Dev Biol. 1985 Sep;111(1):158-70 PMID: 3928418
  35. Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation.
    Cell. 1985 Oct;42(3):841-8 PMID: 2996779
  36. Sarcoma viruses carrying ras oncogenes induce differentiation-associated properties in a neuronal cell line.
    Nature. 1985 Nov 7-13;318(6041):73-5 PMID: 4058592
  37. A genetic pathway for the development of the Caenorhabditis elegans HSN motor neurons.
    Nature. 1988 Dec 15;336(6200):638-46 PMID: 3200316
  38. Movement of internalized ligand-receptor complexes along a continuous endosomal reticulum.
    Nature. 1990 Jul 26;346(6282):335-9 PMID: 2374607
  39. Mutations affecting axonal growth and guidance of motor neurons and mechanosensory neurons in the nematode Caenorhabditis elegans.
    Neurosci Res Suppl. 1990;13:S171-90 PMID: 1701874
  40. Cerebellar granule cell neurogenesis is regulated by cell-cell interactions in vitro.
    Neuron. 1991 May;6(5):705-15 PMID: 2025426
  41. Genes necessary for directed axonal elongation or fasciculation in C. elegans.
    Neuron. 1992 Feb;8(2):307-22 PMID: 1739461
  42. The role of GTP-binding proteins in transport along the exocytic pathway.
    Annu Rev Cell Biol. 1993;9:575-99 PMID: 8280472
  43. Caenorhabditis elegans unc-51 gene required for axonal elongation encodes a novel serine/threonine kinase.
    Genes Dev. 1994 Oct 15;8(20):2389-400 PMID: 7958904
  44. Rab GTPases: master regulators of membrane trafficking.
    Curr Opin Cell Biol. 1994 Aug;6(4):522-6 PMID: 7986528
  45. Localization of Rab5 to synaptic vesicles identifies endosomal intermediate in synaptic vesicle recycling pathway.
    Eur J Cell Biol. 1994 Dec;65(2):319-26 PMID: 7720727
  46. Regulation of receptor-mediated endocytosis by Rho and Rac.
    Nature. 1996 Jul 11;382(6587):177-9 PMID: 8700210
  47. Ras effectors.
    Curr Opin Cell Biol. 1996 Apr;8(2):197-204 PMID: 8791426
  48. The molecular biology of axon guidance.
    Science. 1996 Nov 15;274(5290):1123-33 PMID: 8895455
  49. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae.
    Gene. 1997 Jun 19;192(2):245-50 PMID: 9224897
  50. The UNC-14 protein required for axonal elongation and guidance in Caenorhabditis elegans interacts with the serine/threonine kinase UNC-51.
    Genes Dev. 1997 Jul 15;11(14):1801-11 PMID: 9242488
  51. Syntenin, a PDZ protein that binds syndecan cytoplasmic domains.
    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13683-8 PMID: 9391086
  52. Catalytic domain of the p120 Ras GAP binds to RAb5 and stimulates its GTPase activity.
    J Biol Chem. 1998 Apr 24;273(17):10087-90 PMID: 9553053
  53. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.
    Neuron. 1998 Apr;20(4):683-91 PMID: 9581761
  54. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.
    Neuron. 1998 May;20(5):895-904 PMID: 9620694
  55. GABA(A)-receptor-associated protein links GABA(A) receptors and the cytoskeleton.
    Nature. 1999 Jan 7;397(6714):69-72 PMID: 9892355
  56. The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif.
    J Biol Chem. 1999 Feb 5;274(6):3726-33 PMID: 9920925
  57. Growth cone guidance: first steps towards a deeper understanding.
    Annu Rev Neurosci. 1999;22:351-88 PMID: 10202543
  58. Distinct neurite outgrowth signaling pathways converge on ERK activation.
    Mol Cell Neurosci. 1999 May;13(5):362-78 PMID: 10356298
  59. The SAD-1 kinase regulates presynaptic vesicle clustering and axon termination.
    Neuron. 2001 Jan;29(1):115-29 PMID: 11182085
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1151204
Published
2004-03-01
Epub
2004-00-10
Pages
541-58
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC374236
Subset
IM
Grants
NCRR NIH HHS · P41 RR001192 · United States
NINDS NIH HHS · R01 NS039991 · United States
NINDS NIH HHS · NS39991 · United States
External Links
PubMed source DOI: 10.1101/gad.1151204 PMC Full Text View journal details
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