title: JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis.
abstract: Neurons are highly polarized cells that often project axons a considerable distance. To respond to axonal damage, neurons must transmit a retrograde signal to the nucleus to enable a transcriptional stress response. Here we describe a mechanism by which this signal is propagated through injury-induced stabilization of dual leucine zipper-bearing kinase (DLK/MAP3K12). After neuronal insult, specific sites throughout the length of DLK underwent phosphorylation by c-Jun N-terminal kinases (JNKs), which have been shown to be downstream targets of DLK pathway activity. These phosphorylation events resulted in increased DLK abundance via reduction of DLK ubiquitination, which was mediated by the E3 ubiquitin ligase PHR1 and the de-ubiquitinating enzyme USP9X. Abundance of DLK in turn controlled the levels of downstream JNK signaling and apoptosis. Through this feedback mechanism, the ubiquitin-proteasome system is able to provide an additional layer of regulation of retrograde stress signaling to generate a global cellular response to localized external insults.
authors: Department of Neuroscience, 2 Department of Microchemical Proteomics, and 3 Department of Physiological Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
authors: Sarah
authors: S
authors: Huntwork-Rodriguez
authors: Bei
authors: B
authors: Wang
authors: Trent
authors: T
authors: Watkins
authors: Arundhati Sengupta
authors: AS
authors: Ghosh
authors: Christine D
authors: CD
authors: Pozniak
authors: Daisy
authors: D
authors: Bustos
authors: Kim
authors: K
authors: Newton
authors: Donald S
authors: DS
authors: Kirkpatrick
authors: Joseph W
authors: JW
authors: Lewcock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008970:Molecular Weight; D009409:Nerve Crush; D020932:Nerve Growth Factor / Q000494:pharmacology; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D025801:Ubiquitin; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12; D046988:Proteasome Endopeptidase Complex
references: Dev Cell. 2003 Apr;4(4):521-33
references: 12689591
references: J Biol Chem. 1996 Oct 4;271(40):24788-93
references: 8798750
references: Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):665-70
references: 14704277
references: Neuron. 2007 Nov 21;56(4):604-20
references: 18031680
references: Science. 2009 Feb 6;323(5915):802-6
references: 19164707
references: Neuron. 2007 Nov 8;56(3):488-502
references: 17988632
references: Mol Cell Biol. 2001 Jul;21(14):4713-24
references: 11416147
references: Nature. 2000 Oct 12;407(6805):802-9
references: 11048732
references: J Biol Chem. 2001 Jan 19;276(3):1961-7
references: 11053428
references: Curr Biol. 1999 Feb 11;9(3):116-25
references: 10021384
references: Mol Cell Biol. 1996 Nov;16(11):6486-93
references: 8887677
references: Nucleic Acids Res. 2003 Feb 15;31(4):e12
references: 12582257
references: Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4039-44
references: 23431164
references: J Neuropathol Exp Neurol. 1999 May;58(5):459-71
references: 10331434
references: J Neurosci. 2002 Jun 1;22(11):4335-45
references: 12040039
references: Eur J Neurosci. 2005 Oct;22(8):1881-94
references: 16262628
references: Nature. 2012 Nov 1;491(7422):109-13
references: 23041929
references: J Neurosci. 2008 Jan 16;28(3):672-80
references: 18199767
references: Neuron. 1999 Apr;22(4):667-76
references: 10230788
references: Annu Rev Phys Chem. 2012;63:571-94
references: 22404590
references: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3920-5
references: 8632990
references: Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4045-50
references: 23431148
references: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2837-42
references: 11226327
references: J Neurochem. 2001 Mar;76(5):1439-54
references: 11238729
references: Nature. 2010 Jan 7;463(7277):103-7
references: 20023629
references: J Proteome Res. 2008 Nov;7(11):4756-65
references: 18798661
references: J Exp Zool. 1949 Aug;111(3):457-501
references: 18142378
references: Annu Rev Neurosci. 2005;28:127-56
references: 16022592
references: PLoS Biol. 2012;10(12):e1001440
references: 23226106
references: Chem Biol. 2002 Oct;9(10):1149-59
references: 12401499
references: J Biol Chem. 1996 Jul 12;271(28):16888-96
references: 8663324
references: Curr Biol. 2001 Aug 7;11(15):1176-82
references: 11516948
references: Science. 1994 Feb 11;263(5148):826-8
references: 8303301
references: Neuron. 2012 Jun 21;74(6):1015-22
references: 22726832
references: J Cell Biol. 2011 Sep 5;194(5):751-64
references: 21893599
references: J Biol Chem. 1994 Dec 9;269(49):30808-17
references: 7983011
references: Neuron. 2012 Nov 8;76(3):534-48
references: 23141066
references: J Biol Chem. 2004 Jan 9;279(2):1351-8
references: 14559897
references: Development. 2002 Oct;129(19):4483-95
references: 12223406
references: Neuron. 1998 Apr;20(4):633-47
references: 9581757
references: J Neurosci. 1998 Feb 15;18(4):1428-39
references: 9454852
references: J Neurosci. 2005 Feb 2;25(5):1149-58
references: 15689551
references: Mol Cell Proteomics. 2011 May;10(5):M110.003756
references: 21048196
references: Neuron. 2006 Jul 6;51(1):57-69
references: 16815332
references: Invest Ophthalmol Vis Sci. 1995 Apr;36(5):774-86
references: 7706025
references: Nature. 1996 Jun 13;381(6583):603-6
references: 8637595
references: Cell. 2005 Feb 11;120(3):407-20
references: 15707898
references: Nat Biotechnol. 2006 Oct;24(10):1285-92
references: 16964243
references: J Neurosci. 2012 Dec 5;32(49):17540-53
references: 23223278
references: J Cell Biol. 2005 Feb 28;168(5):775-87
references: 15738268
references: J Neurosci Res. 2007 Jun;85(8):1668-73
references: 17455299
references: Nat Rev Neurosci. 2003 May;4(5):365-75
references: 12728264
references: Nat Neurosci. 2009 Apr;12(4):387-9
references: 19287387
references: Neurobiol Dis. 2012 May;46(2):393-401
references: 22353563
references: Bioessays. 2007 Jan;29(1):85-90
references: 17187378
references: J Cell Biol. 2010 Oct 4;191(1):211-23
references: 20921142
references: Mol Cell Biol. 2002 Jul;22(13):4929-42
references: 12052897
references: J Biol Chem. 2000 Mar 10;275(10):7273-9
references: 10702297
references: Cell Rep. 2013 May 30;3(5):1422-9
references: 23665224
references: Gene Expr Patterns. 2005 Apr;5(4):517-23
references: 15749080
references: Curr Opin Cell Biol. 2002 Apr;14(2):140-8
references: 11891111