title: The microtubule affinity regulating kinase MARK4 promotes axoneme extension during early ciliogenesis.
abstract: Despite the critical contributions of cilia to embryonic development and human health, key regulators of cilia formation await identification. In this paper, a functional RNA interference-based screen linked 30 novel protein kinases with ciliogenesis. Of them, we have studied the role of the microtubule (MT)-associated protein/MT affinity regulating kinase 4 (MARK4) in depth. MARK4 associated with the basal body and ciliary axoneme in human and murine cell lines. Ultrastructural and functional analyses established that MARK4 kinase activity was required for initiation of axoneme extension. We identified the mother centriolar protein ODF2 as an interaction partner of MARK4 and showed that ODF2 localization to the centriole partially depended on MARK4. Our data indicated that, upon MARK4 or ODF2 knockdown, the ciliary program arrested before the complete removal of the CP110-Cep97 inhibitory complex from the mother centriole, suggesting that these proteins act at this level of axonemal extension. We propose that MARK4 is a critical positive regulator of early steps in ciliogenesis.
authors: Molecular Biology of Centrosomes and Cilia group, Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Stefanie
authors: S
authors: Kuhns
authors: Kerstin N
authors: KN
authors: Schmidt
authors: Jürgen
authors: J
authors: Reymann
authors: Daniel F
authors: DF
authors: Gilbert
authors: Annett
authors: A
authors: Neuner
authors: Birgit
authors: B
authors: Hub
authors: Ricardo
authors: R
authors: Carvalho
authors: Philipp
authors: P
authors: Wiedemann
authors: Hanswalter
authors: H
authors: Zentgraf
authors: Holger
authors: H
authors: Erfle
authors: Ursula
authors: U
authors: Klingmüller
authors: Michael
authors: M
authors: Boutros
authors: Gislene
authors: G
authors: Pereira
mesh_terms: D000818:Animals; D054468:Axoneme / Q000378:metabolism* / Q000648:ultrastructure; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference
chemical_list: C467559:CCP110 protein, human; C523555:CEP97 protein, human; D018797:Cell Cycle Proteins; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; C490107:ODF2 protein, human; D010750:Phosphoproteins; C483047:MARK4 protein, human; C482979:MARK4 protein, mouse; D017346:Protein Serine-Threonine Kinases
references: Nat Rev Mol Cell Biol. 2011 Nov 16;12(12):773-86
references: 22086369
references: J Biol Chem. 2004 Feb 13;279(7):5915-23
references: 14594945
references: J Cell Biol. 2004 Aug 30;166(5):637-43
references: 15337773
references: J Cell Sci. 2011 Feb 15;124(Pt 4):600-12
references: 21266464
references: J Cell Biol. 2007 Jul 30;178(3):363-9
references: 17646400
references: J Cell Biol. 2007 Oct 22;179(2):321-30
references: 17954613
references: Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51
references: 1319065
references: Curr Biol. 2009 Sep 15;19(17):1498-502
references: 19682908
references: Sci STKE. 2005 Jan 11;2005(266):pl1
references: 15644491
references: J Cell Biol. 1995 Aug;130(4):919-27
references: 7642707
references: J Cell Biol. 2000 Oct 30;151(3):709-18
references: 11062270
references: Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93
references: 17955020
references: J Cell Sci. 1968 Jun;3(2):207-30
references: 5661997
references: J Cell Biol. 1962 Nov;15:363-77
references: 13978319
references: Nature. 2010 Apr 15;464(7291):1048-51
references: 20393563
references: Curr Biol. 2009 Jun 23;19(12):1005-11
references: 19481458
references: Cell Cycle. 2007 Aug 15;6(16):1966-9
references: 17721078
references: Sci Signal. 2011 Jan 25;4(157):ra4
references: 21266715
references: Nat Cell Biol. 2010 Nov;12(11):1115-22
references: 20972424
references: Nat Rev Mol Cell Biol. 2011 Apr;12(4):222-34
references: 21427764
references: Curr Top Dev Biol. 2008;85:23-61
references: 19147001
references: BMC Syst Biol. 2010 Aug 05;4:106
references: 20687942
references: EMBO J. 2004 Feb 25;23(4):833-43
references: 14976552
references: Trends Genet. 2006 Sep;22(9):491-500
references: 16860433
references: Mol Biol Cell. 2001 Jun;12(6):1687-97
references: 11408577
references: J Cell Biol. 2002 Oct 28;159(2):255-66
references: 12403812
references: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2759-64
references: 21273506
references: Pathogenetics. 2009 May 13;2(1):3
references: 19439065
references: Mol Biol Cell. 2006 Sep;17(9):3781-92
references: 16775004
references: J Cell Biol. 2002 Apr 1;157(1):103-13
references: 11916979
references: Biol Cell. 1994;81(1):11-6
references: 7987237
references: BMC Neurosci. 2008 Dec 03;9 Suppl 2:S9
references: 19090997
references: Nat Cell Biol. 2007 Feb;9(2):160-70
references: 17330329
references: Trends Biochem Sci. 1998 Aug;23(8):307-11
references: 9757832
references: J Cell Biol. 2005 Jun 6;169(5):707-10
references: 15928206
references: Neoplasia. 2001 Jan-Feb;3(1):4-9
references: 11326310
references: Methods Cell Biol. 2009;94:333-46
references: 20362099
references: Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1584-8
references: 14747658
references: Eukaryot Cell. 2009 Jul;8(7):922-32
references: 19429781
references: Trends Biochem Sci. 2009 Jul;34(7):332-42
references: 19559622
references: Mol Cell Proteomics. 2008 Feb;7(2):282-9
references: 17951627
references: Biol Cell. 2004 Apr;96(3):193-9
references: 15182702
references: Cell. 2012 Jan 20;148(1-2):189-200
references: 22265411
references: Neuroscience. 2006 Nov 17;143(1):83-94
references: 16973293
references: Cell. 2007 Aug 24;130(4):678-90
references: 17719545
references: J Cell Biol. 2012 Dec 24;199(7):1083-101
references: 23253480
references: FASEB J. 2010 Jun;24(6):1637-48
references: 20071654
references: Nat Cell Biol. 2005 May;7(5):517-24
references: 15852003
references: Cytoskeleton (Hoboken). 2011 May;68(5):266-78
references: 21491614
references: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6346-51
references: 20308558
references: Cell. 2009 Nov 13;139(4):663-78
references: 19914163
references: Gene Ther. 2002 Apr;9(8):477-87
references: 11948372
references: Biol Cell. 2011 Mar;103(3):131-44
references: 21275905
references: Dev Cell. 2009 Apr;16(4):539-50
references: 19386263
references: Nature. 1984 Nov 15-21;312(5991):232-7
references: 6504137
references: Cancer Res. 2008 Apr 1;68(7):2058-61
references: 18381407
references: Dev Dyn. 2008 Aug;237(8):1972-81
references: 18435467
references: Mol Cell Proteomics. 2007 Mar;6(3):537-47
references: 17192257
references: J Biol Chem. 2004 Mar 26;279(13):12804-11
references: 14676191
references: Mol Biol Cell. 2006 Mar;17(3):1483-93
references: 16407408
references: Mol Biol Cell. 2005 Mar;16(3):1095-107
references: 15616186