title: Phosphorylation of p27Kip1 at Thr187 by cyclin-dependent kinase 5 modulates neural stem cell differentiation.
abstract: Cyclin-dependent kinase 5 (Cdk5) plays a key role in the development of the mammalian nervous system; it phosphorylates a number of targeted proteins involved in neuronal migration during development to synaptic activity in the mature nervous system. Its role in the initial stages of neuronal commitment and differentiation of neural stem cells (NSCs), however, is poorly understood. In this study, we show that Cdk5 phosphorylation of p27(Kip1) at Thr187 is crucial to neural differentiation because 1) neurogenesis is specifically suppressed by transfection of p27(Kip1) siRNA into Cdk5(+/+) NSCs; 2) reduced neuronal differentiation in Cdk5(-/-) compared with Cdk5(+/+) NSCs; 3) Cdk5(+/+) NSCs, whose differentiation is inhibited by a nonphosphorylatable mutant, p27/Thr187A, are rescued by cotransfection of a phosphorylation-mimicking mutant, p27/Thr187D; and 4) transfection of mutant p27(Kip1) (p27/187A) into Cdk5(+/+) NSCs inhibits differentiation. These data suggest that Cdk5 regulates the neural differentiation of NSCs by phosphorylation of p27(Kip1) at theThr187 site. Additional experiments exploring the role of Ser10 phosphorylation by Cdk5 suggest that together with Thr187 phosphorylation, Ser10 phosphorylation by Cdk5 promotes neurite outgrowth as neurons differentiate. Cdk5 phosphorylation of p27(Kip1), a modular molecule, may regulate the progress of neuronal differentiation from cell cycle arrest through differentiation, neurite outgrowth, and migration.
authors.affiliation: Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4130, USA.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Zheng
authors.forename: Bing-Sheng
authors.initials: BS
authors.lastname: Li
authors.forename: Parvathi
authors.initials: P
authors.lastname: Rudrabhatla
authors.forename: Varsha
authors.initials: V
authors.lastname: Shukla
authors.forename: Niranjana D
authors.initials: ND
authors.lastname: Amin
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Jyotshnabala
authors.initials: J
authors.lastname: Kanungo
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Philip
authors.initials: P
authors.lastname: Grant
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology* / Q000201:enzymology*; D016501:Neurites / Q000378:metabolism; D055495:Neurogenesis; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D010769:Phosphothreonine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5
references.citation: Cell Cycle. 2006 Oct;5(20):2314-8
references.pmid: 17102618
references.citation: Mol Neurobiol. 2004 Aug;30(1):49-76
references.pmid: 15247488
references.citation: Nature. 2001 Sep 20;413(6853):323-7
references.pmid: 11565035
references.citation: Bull Mem Acad R Med Belg. 2007;162(5-6):310-4
references.pmid: 18405000
references.citation: Development. 2003 Jan;130(1):85-92
references.pmid: 12441293
references.citation: BMC Neurosci. 2009 Aug 06;10:93
references.pmid: 19660102
references.citation: Dev Biol. 1999 Mar 1;207(1):119-32
references.pmid: 10049569
references.citation: Curr Biol. 1998 Dec 3;8(24):R872-4
references.pmid: 9843675
references.citation: EMBO J. 1997 Sep 1;16(17):5334-44
references.pmid: 9311993
references.citation: Development. 2000 Feb;127(4):693-702
references.pmid: 10648228
references.citation: Curr Protoc Neurosci. 2005 Nov;Chapter 3:Unit 3.18
references.pmid: 18428621
references.citation: Genes Dev. 2006 Jun 1;20(11):1511-24
references.pmid: 16705040
references.citation: EMBO J. 2001 Dec 3;20(23):6672-82
references.pmid: 11726503
references.citation: Cell. 1999 Nov 24;99(5):499-510
references.pmid: 10589678
references.citation: EMBO J. 2005 Jan 12;24(1):209-20
references.pmid: 15592431
references.citation: Nat Cell Biol. 2006 Jan;8(1):17-26
references.pmid: 16341208
references.citation: Development. 2003 Jan;130(1):71-83
references.pmid: 12441292
references.citation: Neurosignals. 2003 Sep-Oct;12(4-5):180-90
references.pmid: 14673204
references.citation: Cell Cycle. 2008 Nov 15;7(22):3487-90
references.pmid: 19001851
references.citation: Science. 1995 Aug 4;269(5224):682-5
references.pmid: 7624798
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11173-8
references.pmid: 8855328
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Science. 1992 Mar 27;255(5052):1707-10
references.pmid: 1553558
references.citation: Mol Biol Cell. 2007 Feb;18(2):404-13
references.pmid: 17108320
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3259-63
references.pmid: 8622924
references.citation: Development. 2006 Feb;133(4):675-84
references.pmid: 16436623
references.citation: Genes Dev. 1997 Jun 1;11(11):1464-78
references.pmid: 9192873
references.citation: J Neurosci. 2007 Feb 21;27(8):1836-52
references.pmid: 17314281
references.citation: EMBO J. 2002 Feb 1;21(3):324-33
references.pmid: 11823425
references.citation: Cell. 2007 Jan 12;128(1):29-43
references.pmid: 17218253
references.citation: Genes Dev. 1999 May 1;13(9):1181-9
references.pmid: 10323868
references.citation: Eur J Biochem. 2002 Sep;269(18):4427-34
references.pmid: 12230554
references.citation: Regen Med. 2009 Nov;4(6):865-77
references.pmid: 19903005
references.citation: Nature. 1994 Sep 29;371(6496):419-23
references.pmid: 8090221
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):507-10
references.pmid: 19497279
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):749-59
references.pmid: 11584302
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18567-71
references.pmid: 19017796
references.citation: Dev Biol. 2007 Jan 1;301(1):14-26
references.pmid: 17123502
references.citation: J Neurosci. 2010 Apr 14;30(15):5219-28
references.pmid: 20392944
references.citation: Regen Med. 2009 Nov;4(6):879-97
references.pmid: 19903006
references.citation: J Biol Chem. 1995 Nov 10;270(45):26897-903
references.pmid: 7592934
references.citation: PLoS Biol. 2008 Nov 11;6(11):e272
references.pmid: 18998770
references.citation: Biochim Biophys Acta. 2004 Mar 11;1697(1-2):143-53
references.pmid: 15023357
references.citation: Cereb Cortex. 2000 Aug;10(8):729-47
references.pmid: 10920046
references.citation: Ment Retard Dev Disabil Res Rev. 2006;12(2):85-96
references.pmid: 16807909
references.citation: Nat Methods. 2005 May;2(5):333-6
references.pmid: 15846359
references.citation: Curr Opin Neurobiol. 1998 Feb;8(1):37-44
references.pmid: 9568390
references.citation: J Neurosci Res. 2005 Jun 1;80(5):600-10
references.pmid: 15884037
references.citation: Dev Neurosci. 2004 Mar-Aug;26(2-4):208-17
references.pmid: 15711061
references.citation: J Neurosci. 2005 Oct 19;25(42):9658-68
references.pmid: 16237170
references.citation: Eur J Biochem. 2001 Mar;268(6):1534-46
references.pmid: 11248670
references.citation: Curr Biol. 1999 Jun 17;9(12):661-4
references.pmid: 10375532
references.citation: J Neurosci. 2003 Jan 1;23(1):240-51
references.pmid: 12514221