title: c-Jun N-terminal kinase phosphorylation of heterogeneous nuclear ribonucleoprotein K regulates vertebrate axon outgrowth via a posttranscriptional mechanism.
abstract: c-Jun N-terminal kinase (JNK) mediates cell signaling essential for axon outgrowth, but the associated substrates and underlying mechanisms are poorly understood. We identified in Xenopus laevis embryos a novel posttranscriptional mechanism whereby JNK regulates axonogenesis by phosphorylating a specific site on heterogeneous nuclear ribonucleoprotein K (hnRNP K). Both JNK inhibition and hnRNP K knockdown inhibited axon outgrowth and translation of hnRNP K-regulated cytoskeletal RNAs (tau and neurofilament medium), effects that were alleviated by expressing phosphomimetic, but not phosphodeficient, forms of hnRNP K. Immunohistochemical and biochemical analyses indicated that JNK phosphorylation of hnRNP K occurred within the cytoplasm and was necessary for the translational initiation of hnRNP K-targeted RNAs but not for hnRNP K intracellular localization or RNA binding. Thus, in addition to its known roles in transcription and cytoskeletal organization, JNK acts posttranscriptionally through hnRNP K to regulate translation of proteins crucial for axonogenesis.
authors.affiliation: Department of Biological Sciences and the Center for Neuroscience Research, University at Albany, State University of New York, Albany, New York 12222.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Hutchins
authors.forename: Ben G
authors.initials: BG
authors.lastname: Szaro
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D019521:Body Patterning / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000196:embryology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054259:Neural Tube / Q000166:cytology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D064531:Peripherins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D009419:Nerve Tissue Proteins; C578995:PRPH protein, Xenopus; D064531:Peripherins; D029867:Xenopus Proteins; D048031:JNK Mitogen-Activated Protein Kinases
references.citation: J Neurosci. 2000 Oct 15;20(20):7602-13
references.pmid: 11027220
references.citation: Neuron. 1999 Apr;22(4):667-76
references.pmid: 10230788
references.citation: FEBS Lett. 1997 Jun 2;409(1):57-62
references.pmid: 9199504
references.citation: Microbiol Mol Biol Rev. 2006 Dec;70(4):1061-95
references.pmid: 17158707
references.citation: Nucleic Acids Res. 1993 Mar 11;21(5):1193-8
references.pmid: 8464704
references.citation: J Neurosci. 2006 Sep 13;26(37):9462-70
references.pmid: 16971530
references.citation: Mol Cell Neurosci. 2003 Sep;24(1):238-49
references.pmid: 14550783
references.citation: Neuron. 1994 Apr;12(4):873-84
references.pmid: 7512817
references.citation: Biol Cell. 2004 Aug;96(6):407-11
references.pmid: 15384226
references.citation: Nat Rev Neurosci. 2012 Apr 13;13(5):308-24
references.pmid: 22498899
references.citation: J Biol Chem. 2004 Nov 26;279(48):49680-8
references.pmid: 15364910
references.citation: Cell. 2009 Sep 4;138(5):1005-18
references.pmid: 19737525
references.citation: Exp Cell Res. 2004 Jan 1;292(1):135-50
references.pmid: 14720513
references.citation: J Comp Neurol. 1994 May 1;343(1):158-72
references.pmid: 7517961
references.citation: Cell. 1997 May 16;89(4):597-606
references.pmid: 9160751
references.citation: J Neurosci. 2010 Jun 9;30(23):7804-16
references.pmid: 20534829
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Neuroscience. 2008 Apr 22;153(1):144-53
references.pmid: 18358619
references.citation: Bioessays. 2004 Jun;26(6):629-38
references.pmid: 15170860
references.citation: J Biol Chem. 2008 Jun 27;283(26):18461-72
references.pmid: 18441016
references.citation: J Cell Sci. 2000 Feb;113 ( Pt 3):401-7
references.pmid: 10639328
references.citation: Nat Cell Biol. 2001 Mar;3(3):325-30
references.pmid: 11231586
references.citation: Am J Physiol Renal Physiol. 2007 Aug;293(2):F607-15
references.pmid: 17581920
references.citation: Brain Res Dev Brain Res. 1989 Jul 1;48(1):87-103
references.pmid: 2502330
references.citation: Prog Neurobiol. 2006 Oct;80(2):84-97
references.pmid: 17045385
references.citation: Neuron. 2004 Jul 8;43(1):1-2
references.pmid: 15233911
references.citation: J Biol Chem. 2001 May 25;276(21):18090-5
references.pmid: 11259409
references.citation: J Neurosci. 1996 Jun 1;16(11):3601-19
references.pmid: 8642405
references.citation: Cell Motil Cytoskeleton. 2001 May;49(1):16-32
references.pmid: 11309837
references.citation: Mol Cell Biol. 2002 Jul;22(13):4535-43
references.pmid: 12052863
references.citation: Cold Spring Harb Perspect Biol. 2010 Apr;2(4):a001925
references.pmid: 20452947
references.citation: Int J Dev Neurosci. 2004 Nov;22(7):559-64
references.pmid: 15465286
references.citation: Cell Signal. 2008 May;20(5):969-77
references.pmid: 18295448
references.citation: EMBO J. 1997 Jun 16;16(12):3587-98
references.pmid: 9218800
references.citation: Development. 2008 Sep;135(18):3125-35
references.pmid: 18725517
references.citation: Hear Res. 2011 Aug;278(1-2):77-85
references.pmid: 21554942
references.citation: Nat Protoc. 2008;3(6):1101-8
references.pmid: 18546601
references.citation: Science. 2009 Feb 6;323(5915):802-6
references.pmid: 19164707
references.citation: J Neurosci. 2006 Aug 2;26(31):8017-20
references.pmid: 16885215
references.citation: J Biol Chem. 2000 Feb 4;275(5):3619-28
references.pmid: 10652358
references.citation: J Neurosci. 2012 Mar 7;32(10):3563-74
references.pmid: 22399778
references.citation: J Neurochem. 2008 Feb;104(4):957-69
references.pmid: 17973977
references.citation: J Neurosci. 2006 Oct 18;26(42):10626-30
references.pmid: 17050700
references.citation: Development. 2011 Jul;138(14):3079-90
references.pmid: 21693523
references.citation: J Neurobiol. 1994 Oct;25(10):1235-48
references.pmid: 7815056
references.citation: Glia. 2003 Apr 15;42(2):184-93
references.pmid: 12655602
references.citation: Mol Cell Neurosci. 1999 May;13(5):362-78
references.pmid: 10356298
references.citation: Dev Biol. 1996 Oct 10;179(1):197-211
references.pmid: 8873764
references.citation: Neuroreport. 2005 May 31;16(8):823-8
references.pmid: 15891578
references.citation: J Comp Neurol. 2003 Oct 13;465(2):161-3
references.pmid: 12949777
references.citation: J Mol Biol. 2006 Aug 18;361(3):470-81
references.pmid: 16854432
references.citation: Neuroscience. 2009 Jul 21;161(4):951-9
references.pmid: 19364525
references.citation: Behav Res Methods. 2007 May;39(2):175-91
references.pmid: 17695343
references.citation: Brain Res. 2009 Jan 23;1250:27-40
references.pmid: 19027722
references.citation: J Biol Chem. 1999 May 21;274(21):15101-9
references.pmid: 10329716
references.citation: J Biol Chem. 2005 Apr 1;280(13):12690-9
references.pmid: 15671036
references.citation: RNA. 2004 Nov;10(11):1751-63
references.pmid: 15496522
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16313-8
references.pmid: 17060633
references.citation: Proteomics. 2006 Apr;6(8):2395-406
references.pmid: 16518874
references.citation: Cell. 2001 Jan 26;104(2):281-90
references.pmid: 11207368
references.citation: Biochem Biophys Res Commun. 2009 May 29;383(2):258-62
references.pmid: 19358824
references.citation: Methods Cell Biol. 2004;78:673-701
references.pmid: 15646635
references.citation: J Comp Neurol. 1996 Jan 08;364(2):219-30
references.pmid: 8788246
references.citation: Trends Neurosci. 2010 Jan;33(1):27-37
references.pmid: 19906448
references.citation: J Neurosci. 2005 Jun 8;25(23):5604-10
references.pmid: 15944388