title: JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors.
abstract: Regulation of the opposing kinesin and dynein motors that drive axonal transport is essential to maintain neuronal homeostasis. Here, we examine coordination of motor activity by the scaffolding protein JNK-interacting protein 1 (JIP1), which we find is required for long-range anterograde and retrograde amyloid precursor protein (APP) motility in axons. We identify novel interactions between JIP1 and kinesin heavy chain (KHC) that relieve KHC autoinhibition, activating motor function in single molecule assays. The direct binding of the dynactin subunit p150(Glued) to JIP1 competitively inhibits KHC activation in vitro and disrupts the transport of APP in neurons. Together, these experiments support a model whereby JIP1 coordinates APP transport by switching between anterograde and retrograde motile complexes. We find that mutations in the JNK-dependent phosphorylation site S421 in JIP1 alter both KHC activation in vitro and the directionality of APP transport in neurons. Thus phosphorylation of S421 of JIP1 serves as a molecular switch to regulate the direction of APP transport in neurons.
authors.affiliation: Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Meng-meng
authors.initials: MM
authors.lastname: Fu
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D002478:Cells, Cultured; D004398:Dyneins / Q000378:metabolism*; D016547:Kinesins / Q000378:metabolism*; D051379:Mice
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C490665:Mapk8ip protein, mouse; D004398:Dyneins; D016547:Kinesins
references.citation: Cell Res. 2009 Dec;19(12):1334-49
references.pmid: 19935774
references.citation: Neuron. 2012 Apr 26;74(2):331-43
references.pmid: 22542186
references.citation: J Neurosci. 2011 Feb 9;31(6):2216-24
references.pmid: 21307258
references.citation: Biophys J. 2007 Jun 15;92(12):4137-44
references.pmid: 17400704
references.citation: J Neurosci. 2009 May 6;29(18):5758-67
references.pmid: 19420244
references.citation: J Biol Chem. 1995 Dec 1;270(48):28806-11
references.pmid: 7499404
references.citation: J Biol Chem. 2002 Feb 1;277(5):3767-75
references.pmid: 11724784
references.citation: Cell. 1989 Mar 10;56(5):867-78
references.pmid: 2522351
references.citation: Mol Cell Proteomics. 2006 Jan;5(1):97-113
references.pmid: 16195223
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19381-6
references.pmid: 19864630
references.citation: Science. 2005 Feb 25;307(5713):1282-8
references.pmid: 15731448
references.citation: Curr Biol. 2010 Apr 27;20(8):697-702
references.pmid: 20399099
references.citation: Cell. 2000 Nov 10;103(4):583-94
references.pmid: 11106729
references.citation: J Cell Biol. 2001 Mar 5;152(5):959-70
references.pmid: 11238452
references.citation: Science. 2011 Aug 12;333(6044):883-5
references.pmid: 21836017
references.citation: J Biol Chem. 2006 Feb 10;281(6):3552-9
references.pmid: 16339760
references.citation: Curr Biol. 2008 Feb 12;18(3):221-6
references.pmid: 18261906
references.citation: J Neurosci. 2009 Aug 5;29(31):9903-17
references.pmid: 19657041
references.citation: J Cell Sci. 1993 Mar;104 ( Pt 3):917-27
references.pmid: 8314882
references.citation: Biochemistry. 2009 Apr 21;48(15):3448-56
references.pmid: 19320433
references.citation: Science. 1997 Aug 1;277(5326):693-6
references.pmid: 9235893
references.citation: Traffic. 2008 May;9(5):725-41
references.pmid: 18266909
references.citation: J Neurosci. 2005 Apr 13;25(15):3741-51
references.pmid: 15829626
references.citation: J Cell Biol. 2006 May 22;173(4):545-57
references.pmid: 16717129
references.citation: Curr Biol. 2007 Aug 7;17(15):1313-7
references.pmid: 17658258
references.citation: Nat Rev Mol Cell Biol. 2009 Nov;10(11):765-77
references.pmid: 19851335
references.citation: Biochem Soc Trans. 2006 Nov;34(Pt 5):828-32
references.pmid: 17052208
references.citation: Nat Cell Biol. 1999 Sep;1(5):293-7
references.pmid: 10559942
references.citation: J Biol Chem. 2009 Dec 11;284(50):34628-39
references.pmid: 19801628
references.citation: Hum Mol Genet. 1997 Dec;6(13):2205-12
references.pmid: 9361024
references.citation: Mol Biol Cell. 2012 May;23(9):1700-14
references.pmid: 22398725
references.citation: J Cell Biol. 2007 Jan 1;176(1):11-7
references.pmid: 17200414
references.citation: Traffic. 2012 Jun;13(6):834-48
references.pmid: 22404616
references.citation: J Neurosci. 2001 Sep 1;21(17):6597-607
references.pmid: 11517249
references.citation: J Biol Chem. 2003 Aug 1;278(31):28694-702
references.pmid: 12756254
references.citation: Bioessays. 2008 Jan;30(1):10-4
references.pmid: 18081006
references.citation: Neuron. 2010 Jan 14;65(1):53-65
references.pmid: 20152113
references.citation: Neuron. 2010 Nov 18;68(4):610-38
references.pmid: 21092854
references.citation: J Neurosci. 2000 Sep 1;20(17):6374-84
references.pmid: 10964943
references.citation: EMBO J. 2006 Feb 22;25(4):785-97
references.pmid: 16456539
references.citation: Neuron. 2013 Feb 6;77(3):485-502
references.pmid: 23395375
references.citation: Mol Biol Cell. 2000 Apr;11(4):1213-24
references.pmid: 10749925
references.citation: Phys Biol. 2004 Jun;1(1-2):R1-11
references.pmid: 16204815
references.citation: Nature. 2009 Feb 19;457(7232):981-9
references.pmid: 19225519
references.citation: J Cell Biol. 2007 Feb 12;176(4):459-71
references.pmid: 17283181
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8938-43
references.pmid: 18579780
references.citation: EMBO J. 2008 Aug 6;27(15):2124-34
references.pmid: 18615096
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10045-50
references.pmid: 17548833
references.citation: J Cell Biol. 2005 Feb 28;168(5):775-87
references.pmid: 15738268
references.citation: EMBO J. 2011 Jul 12;30(16):3416-29
references.pmid: 21750526
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4609-14
references.pmid: 18347340
references.citation: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8582-7
references.pmid: 22582169
references.citation: Nat Neurosci. 2009 May;12(5):559-67
references.pmid: 19377471
references.citation: Science. 2008 Feb 22;319(5866):1086-9
references.pmid: 18202255
references.citation: J Cell Biol. 2012 Feb 20;196(4):407-17
references.pmid: 22331844
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12913-8
references.pmid: 17646655
references.citation: Cell. 2011 Feb 18;144(4):551-65
references.pmid: 21335237
references.citation: Curr Biol. 2004 Jul 13;14(13):R525-37
references.pmid: 15242636
references.citation: J Cell Biol. 1998 Nov 16;143(4):1053-66
references.pmid: 9817761
references.citation: Dev Cell. 2009 Jul;17(1):110-22
references.pmid: 19619496
references.citation: J Cell Biol. 2005 Nov 21;171(4):615-25
references.pmid: 16301330
references.citation: Traffic. 2013 Mar;14(3):295-308
references.pmid: 23279138
references.citation: Science. 2012 Nov 2;338(6107):662-5
references.pmid: 23065903
references.citation: Curr Biol. 2005 Dec 6;15(23):2137-41
references.pmid: 16332540
references.citation: Nat Cell Biol. 2005 Jan;7(1):48-55
references.pmid: 15580264
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):501-6
references.pmid: 23267076