title: Gauchos and ochos: a Wee1-Cdk tango regulating mitotic entry.
abstract: The kinase Wee1 has been recognized for a quarter century as a key inhibitor of Cyclin dependent kinase 1 (Cdk1) and mitotic entry in eukaryotes. Nonetheless, Wee1 regulation is not well understood and its large amino-terminal regulatory domain (NRD) has remained largely uncharted. Evidence has accumulated that cyclin B/Cdk1 complexes reciprocally inhibit Wee1 activity through NRD phosphorylation. Recent studies have identified the first functional NRD elements and suggested that vertebrate cyclin A/Cdk2 complexes also phosphorylate the NRD. A short NRD peptide, termed the Wee box, augments the activity of the Wee1 kinase domain. Cdk1/2-mediated phosphorylation of the Wee box (on T239) antagonizes kinase activity. A nearby region harbors a conserved RxL motif (RxL1) that promotes cyclin A/Cdk2 binding and T239 phosphorylation. Mutation of either T239 or RxL1 bolsters the ability of Wee1 to block mitotic entry, consistent with negative regulation of Wee1 through these sites. The region in human somatic Wee1 that encompasses RxL1 also binds Crm1, directing Wee1 export from the nucleus. These studies have illuminated important aspects of Wee1 regulation and defined a specific molecular pathway through which cyclin A/Cdk2 complexes foster mitotic entry. The complexity, speed, and importance of regulation of mitotic entry suggest that there is more to be learned.
authors.affiliation: Department of Medicine, Fox Chase Cancer Center, 333 Cottman, Philadelphia, PA 19111, USA. greg.enders@fccc.edu.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Enders
references.citation: EMBO J. 1995 May 15;14(10):2166-75
references.pmid: 7774574
references.citation: Curr Biol. 2003 Oct 14;13(20):1775-85
references.pmid: 14561402
references.citation: Cell Cycle. 2005 Nov;4(11):1491-4
references.pmid: 16258277
references.citation: J Cell Biol. 1999 Oct 18;147(2):295-306
references.pmid: 10525536
references.citation: J Biol Chem. 2003 Oct 17;278(42):40815-28
references.pmid: 12912980
references.citation: Science. 2000 May 26;288(5470):1425-9
references.pmid: 10827953
references.citation: Mol Cell Biol. 1997 Aug;17(8):4338-45
references.pmid: 9234691
references.citation: Mol Cell Biol. 2010 Jan;30(1):116-30
references.pmid: 19858290
references.citation: Mol Cell Biol. 2001 Aug;21(15):4868-74
references.pmid: 11438644
references.citation: Cell. 1987 May 22;49(4):559-67
references.pmid: 3032459
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4419-24
references.pmid: 15070733
references.citation: EMBO J. 2002 May 15;21(10):2472-84
references.pmid: 12006499
references.citation: Cell. 1993 Aug 13;74(3):463-74
references.pmid: 8348613
references.citation: Dev Biol. 2000 Nov 15;227(2):706-19
references.pmid: 11071785
references.citation: Mol Cell. 2010 Mar 26;37(6):753-67
references.pmid: 20347419
references.citation: Mol Biol Cell. 2003 Jan;14(1):201-13
references.pmid: 12529437
references.citation: Mol Cell Biol. 2001 Apr;21(8):2755-66
references.pmid: 11283255
references.citation: J Biol Chem. 1996 May 31;271(22):13283-91
references.pmid: 8662825
references.citation: Mol Cell Biol. 2005 Jul;25(13):5725-37
references.pmid: 15964826
references.citation: Nature. 2001 Nov 29;414(6863):514-21
references.pmid: 11734846
references.citation: Mol Cell. 2000 Sep;6(3):649-59
references.pmid: 11030344
references.citation: Mol Cell. 2003 Apr;11(4):845-6
references.pmid: 12718868
references.citation: Oncogene. 2004 Apr 22;23(19):3361-7
references.pmid: 14767478
references.citation: Mol Biol Cell. 2007 May;18(5):1861-73
references.pmid: 17344473
references.citation: Cell. 2007 Mar 23;128(6):1133-45
references.pmid: 17382882
references.citation: Mol Cell Biol. 1999 Sep;19(9):6183-94
references.pmid: 10454565
references.citation: J Biol Chem. 2001 Jan 19;276(3):1993-7
references.pmid: 11067844
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3753-8
references.pmid: 17360425
references.citation: Cell Cycle. 2007 Nov 15;6(22):2795-9
references.pmid: 18032919
references.citation: Cell. 2009 Jul 23;138(2):352-65
references.pmid: 19592082
references.citation: Mol Cell Biol. 2005 Dec;25(23):10580-90
references.pmid: 16287869
references.citation: Cell Cycle. 2006 Mar;5(6):661-6
references.pmid: 16582612
references.citation: Cancer Res. 2001 Oct 1;61(19):7325-32
references.pmid: 11585773
references.citation: Science. 1995 Oct 6;270(5233):86-90
references.pmid: 7569953
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10453-8
references.pmid: 9724724
references.citation: Science. 1998 Dec 4;282(5395):1886-9
references.pmid: 9836638
references.citation: Nature. 2009 Apr 30;458(7242):1136-41
references.pmid: 19339969
references.citation: Cancer Cell. 2003 Mar;3(3):233-45
references.pmid: 12676582
references.citation: Science. 2009 May 22;324(5930):1087-91
references.pmid: 19389996
references.citation: Nat Cell Biol. 2003 Apr;5(4):346-51
references.pmid: 12629549
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11663-8
references.pmid: 16085715
references.citation: Cell. 2005 Aug 12;122(3):407-20
references.pmid: 16096060
references.citation: J Cell Sci. 2003 Dec 15;116(Pt 24):4883-90
references.pmid: 14625382
references.citation: EMBO J. 1992 Mar;11(3):961-71
references.pmid: 1312467
references.citation: EMBO J. 1995 May 1;14(9):1878-91
references.pmid: 7743995
references.citation: Cell. 2009 Aug 21;138(4):760-73
references.pmid: 19703401
references.citation: Nature. 2008 Jul 17;454(7202):288-9
references.pmid: 18633407
references.citation: Mol Cell Biol. 1999 Feb;19(2):1068-80
references.pmid: 9891042