The regulation of cell size is critical to ensure functionality of a cell. Besides environmental factors such as nutrients, growth factors and functional load, cell size is also controlled by a cellular cell size checkpoint.
Wee1 is a component of this checkpoint. It is a kinase determining the timepoint of entry into mitosis, thus influencing the size of the daughter cells. Loss of Wee1 function will produce smaller than normal daughter cell, because cell division occurs prematurely.
Its name is derived from the Scottishdialect word wee, meaning small - its discoverer Paul Nurse was working at the University of Edinburgh in Scotland at the time of discovery.[1][2]
Function
Fig. 1 Role and regulation of Wee1
Wee1 inhibits Cdk1 by phosphorylating it on two different sites, Tyr15 and Thr14.[3] Cdk1 is crucial for the cyclin-dependent passage of the various cell cycle checkpoints. At least three checkpoints exist for which the inhibition of Cdk1 by Wee1 is important:
G2/M checkpoint: Wee1 phosphorylates the amino acids Tyr15 and Thr14 of Cdk1, which keeps the kinase activity of Cdk1 low and prevents entry into mitosis; in S. pombe further cell growth can occur. Wee1 mediated inactivation of Cdk1 has been shown to be ultrasensitive as a result of substrate competition.[4] During mitotic entry the activity of Wee1 is decreased by several regulators and thus Cdk1 activity is increased. In S. pombe, Pom1, a protein kinase, localizes to the cell poles. This activates a pathway in which Cdr2 inhibits Wee1 through Cdr1. Cdk1 itself negatively regulates Wee1 by phosphorylation, which leads to a positive feedback loop. The decreased Wee1 activity alone is not sufficient for mitotic entry: Synthesis of cyclins and an activating phosphorylation by a Cdk activating kinase (CAK) are also required.[5]
Cell size checkpoint: There is evidence for the existence of a cell size checkpoint, which prevents small cells from entering mitosis. Wee1 plays a role in this checkpoint by coordinating cell size and cell cycle progression.[6]
DNA damage checkpoint: This checkpoint also controls the G2/M transition. In S. pombe this checkpoint delays the mitosis entry of cells with DNA damage (for example induced by gamma radiation). The lengthening of the G2 phase depends on Wee1; wee1 mutants have no prolonged G2 phase after gamma irradiation.[7]
Epigenetic function of Wee1 kinase has also been reported. Wee1 was shown to phosphorylate histone H2B at tyrosine 37 residue which regulated global expression of histones.[8][9]
The WEE1 gene has two known homologues in humans, WEE1 (also known as WEE1A) and WEE2 (WEE1B). The corresponding proteins are Wee1-like protein kinase and Wee1-like protein kinase 2 which act on the human Cdk1 homologue Cdk1.
In S. pombe, Wee1 is phosphorylated Cdk1 and cyclin B make up the maturation promoting factor (MPF) which promotes the entry into mitosis. It is inactivated by phosphorylation through Wee1 and activated by the phosphatase Cdc25C. Cdc25C in turn is activated by Polo kinase and inactivated by Chk1.[6] Thus in S. pombe Wee1 regulation is mainly under the control of phosphorylation through the polarity kinase, Pom1's, pathway including Cdr2 and Cdr1.[10][11][12][13]
At the G2/M transition, Cdk1 is activated by Cdc25 through dephosphorylation of Tyr15. At the same time, Wee1 is inactivated through phosphorylation at its C-terminal catalytic domain by Nim1/Cdr1.[12] Also, the active MPF will promote its own activity by activating Cdc25 and inactivating Wee1, creating a positive feedback loop, though this is not yet understood in detail.[6]
Higher eukaryotes regulate Wee1 via phosphorylation and degradation In higher eukaryotes, Wee1 inactivation occurs both by phosphorylation and degradation.[14] The protein complex[nb 1]SCFβ-TrCP1/2 is an E3 ubiquitin ligase that functions in Wee1A ubiquitination. The M-phase kinases Polo-like kinase (Plk1) and Cdc2 phosphorylate two serine residues in Wee1A which are recognized by SCFβ-TrCP1/2.[15]
S. cerevisiae homologue Swe1 In S. cerevisiae, cyclin-dependent kinase Cdc28 (Cdk1 homologue) is phosphorylated by Swe1 (Wee1 homologue) and dephosphorylated by Mih1 (Cdc25 homologue). Nim1/Cdr1 homologue in S. cerevisiae, Hsl1, together with its related kinases Gin4 and Kcc4 localize Swe1 to the bud-neck. Bud-neck associating kinases Cla4 and Cdc5 (polo kinase homologue) phosphorylate Swe1 at different stages of the cell cycle. Swe1 is also phosphorylated by Clb2-Cdc28 which serves as a recognition for further phosphorylation by Cdc5.
The S. cerevisiae protein Swe1 is also regulated by degradation. Swe1 is hyperphosphorylated by Clb2-Cdc28 and Cdc5 which may be a signal for ubiquitination and degradation by SCF E3 ubiquitin ligase complex as in higher eukaryotes.[16]
Role in cancer
The mitosis promoting factor MPF also regulates DNA-damage induced apoptosis. Negative regulation of MPF by WEE1 causes aberrant mitosis and thus resistance to DNA-damage induced apoptosis. Kruppel-like factor 2 (KLF2) negatively regulates human WEE1, thus increasing sensitivity to DNA-damage induced apoptosis in cancer cells.[17]
Mutant phenotype
Wee1 acts as a dosage-dependent inhibitor of mitosis.[18] Thus, the amount of Wee1 protein correlates with the size of the cells:
The fission yeast mutantwee1, also called wee1−, divides at a significantly smaller cell size than wildtype cells. Since Wee1 inhibits entry into mitosis, its absence will lead to division at a premature stage and sub-normal cell size. Conversely, when Wee1 expression is increased, mitosis is delayed and cells grow to a large size before dividing.
^Nurse P, Thuriaux P (November 1980). "Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe". Genetics. 96 (3): 627–37. doi:10.1093/genetics/96.3.627. PMC1214365. PMID 7262540.
^Den Haese GJ, Walworth N, Carr AM, Gould KL (1995). "The Wee1 protein kinase regulates T14 phosphorylation of fission yeast Cdc2". Mol Biol Cell. 6 (4): 371–85. doi:10.1091/mbc.6.4.371. PMC301198. PMID 7626804.
^Kim, SY; Ferrell JE, Jr (23 March 2007). "Substrate competition as a source of ultrasensitivity in the inactivation of Wee1". Cell. 128 (6): 1133–45. doi:10.1016/j.cell.2007.01.039. PMID 17382882. S2CID 14138576.
^Coleman TR, Dunphy WG (1994). "Cdc2 regulatory factors". Current Opinion in Cell Biology. 6 (6): 877–82. doi:10.1016/0955-0674(94)90060-4. PMID 7880537.
^ abcKellogg DR (2003). "Wee1-dependent mechanisms required for coordination of cell growth and cell division". J Cell Sci. 116 (24): 4883–90. doi:10.1242/jcs.00908. PMID 14625382.
^Rowley R, Hudson J, Young PG (1992). "The wee1 protein kinase is required for radiation-induced mitotic delay". Nature. 356 (6367): 353–5. Bibcode:1992Natur.356..353R. doi:10.1038/356353a0. PMID 1549179. S2CID 4280074.
^Boddy MN, Furnari B, Mondesert O, Russell P (May 1998). "Replication checkpoint enforced by kinases Cds1 and Chk1". Science. 280 (5365): 909–12. Bibcode:1998Sci...280..909B. doi:10.1126/science.280.5365.909. PMID 9572736.
^Wu L, Russell P (June 1993). "Nim1 kinase promotes mitosis by inactivating Wee1 tyrosine kinase". Nature. 363 (6431): 738–41. Bibcode:1993Natur.363..738W. doi:10.1038/363738a0. PMID 8515818. S2CID 4320080.
^ abColeman TR, Tang Z, Dunphy WG (March 1993). "Negative regulation of the wee1 protein kinase by direct action of the nim1/cdr1 mitotic inducer". Cell. 72 (6): 919–29. doi:10.1016/0092-8674(93)90580-J. PMID 7681363. S2CID 42256641.
^Tang Z, Coleman TR, Dunphy WG (September 1993). "Two distinct mechanisms for negative regulation of the Wee1 protein kinase". EMBO J. 12 (9): 3427–36. doi:10.1002/j.1460-2075.1993.tb06017.x. PMC413619. PMID 7504624.
^Watanabe N, Broome M, Hunter T (May 1995). "Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle". EMBO J. 14 (9): 1878–91. doi:10.1002/j.1460-2075.1995.tb07180.x. PMC398287. PMID 7743995.
^Watanabe N, Arai H, Nishihara Y, et al. (March 2004). "M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP". Proc. Natl. Acad. Sci. U.S.A. 101 (13): 4419–24. Bibcode:2004PNAS..101.4419W. doi:10.1073/pnas.0307700101. PMC384762. PMID 15070733.
^Lee KS, Asano S, Park JE, Sakchaisri K, Erikson RL (October 2005). "Monitoring the cell cycle by multi-kinase-dependent regulation of Swe1/Wee1 in budding yeast". Cell Cycle. 4 (10): 1346–9. doi:10.4161/cc.4.10.2049. PMID 16123596.
^Wang F, Zhu Y, Huang Y, et al. (June 2005). "Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis". Oncogene. 24 (24): 3875–85. doi:10.1038/sj.onc.1208546. PMID 15735666.
^Russell P, Nurse P (May 1987). "Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog". Cell. 49 (4): 559–67. doi:10.1016/0092-8674(87)90458-2. PMID 3032459. S2CID 42801276.
wee1, nuclear, kinase, belonging, family, protein, kinases, fission, yeast, schizosaccharomyces, pombe, pombe, molecular, mass, regulator, cell, cycle, progression, influences, cell, size, inhibiting, entry, into, mitosis, through, inhibiting, cdk1, homologues. Wee1 is a nuclear kinase belonging to the Ser Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe S pombe Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression It influences cell size by inhibiting the entry into mitosis through inhibiting Cdk1 Wee1 has homologues in many other organisms including mammals Wee1Crystal structure of human Wee1IdentifiersSymbolMitosis inhibitor protein kinase Wee1Alt symbolswee1 dual specificity protein kinase Wee1NCBI gene2539123UniProtP07527Other dataEC number2 7 11 1Search forStructuresSwiss modelDomainsInterPro Contents 1 Introduction 2 Function 3 Homologues 4 Regulation 5 Role in cancer 6 Mutant phenotype 7 See also 8 Notes 9 References 10 External linksIntroduction EditThe regulation of cell size is critical to ensure functionality of a cell Besides environmental factors such as nutrients growth factors and functional load cell size is also controlled by a cellular cell size checkpoint Wee1 is a component of this checkpoint It is a kinase determining the timepoint of entry into mitosis thus influencing the size of the daughter cells Loss of Wee1 function will produce smaller than normal daughter cell because cell division occurs prematurely Its name is derived from the Scottish dialect word wee meaning small its discoverer Paul Nurse was working at the University of Edinburgh in Scotland at the time of discovery 1 2 Function Edit Fig 1 Role and regulation of Wee1 Wee1 inhibits Cdk1 by phosphorylating it on two different sites Tyr15 and Thr14 3 Cdk1 is crucial for the cyclin dependent passage of the various cell cycle checkpoints At least three checkpoints exist for which the inhibition of Cdk1 by Wee1 is important G2 M checkpoint Wee1 phosphorylates the amino acids Tyr15 and Thr14 of Cdk1 which keeps the kinase activity of Cdk1 low and prevents entry into mitosis in S pombe further cell growth can occur Wee1 mediated inactivation of Cdk1 has been shown to be ultrasensitive as a result of substrate competition 4 During mitotic entry the activity of Wee1 is decreased by several regulators and thus Cdk1 activity is increased In S pombe Pom1 a protein kinase localizes to the cell poles This activates a pathway in which Cdr2 inhibits Wee1 through Cdr1 Cdk1 itself negatively regulates Wee1 by phosphorylation which leads to a positive feedback loop The decreased Wee1 activity alone is not sufficient for mitotic entry Synthesis of cyclins and an activating phosphorylation by a Cdk activating kinase CAK are also required 5 Cell size checkpoint There is evidence for the existence of a cell size checkpoint which prevents small cells from entering mitosis Wee1 plays a role in this checkpoint by coordinating cell size and cell cycle progression 6 DNA damage checkpoint This checkpoint also controls the G2 M transition In S pombe this checkpoint delays the mitosis entry of cells with DNA damage for example induced by gamma radiation The lengthening of the G2 phase depends on Wee1 wee1 mutants have no prolonged G2 phase after gamma irradiation 7 Epigenetic function of Wee1 kinase has also been reported Wee1 was shown to phosphorylate histone H2B at tyrosine 37 residue which regulated global expression of histones 8 9 Homologues Edithuman WEE1 homolog S pombe IdentifiersSymbolWEE1NCBI gene7465HGNC12761OMIM193525RefSeqNM 003390UniProtP30291Other dataLocusChr 11 p15 3 15 1Search forStructuresSwiss modelDomainsInterProhuman WEE1 homolog 2 S pombe IdentifiersSymbolWEE2NCBI gene494551HGNC19684RefSeqNM 001105558UniProtP0C1S8Other dataLocusChr 7 q32 q32Search forStructuresSwiss modelDomainsInterProThe WEE1 gene has two known homologues in humans WEE1 also known as WEE1A and WEE2 WEE1B The corresponding proteins are Wee1 like protein kinase and Wee1 like protein kinase 2 which act on the human Cdk1 homologue Cdk1 The homologue to Wee1 in budding yeast Saccharomyces cerevisiae is called Swe1 Regulation EditIn S pombe Wee1 is phosphorylatedCdk1 and cyclin B make up the maturation promoting factor MPF which promotes the entry into mitosis It is inactivated by phosphorylation through Wee1 and activated by the phosphatase Cdc25C Cdc25C in turn is activated by Polo kinase and inactivated by Chk1 6 Thus in S pombe Wee1 regulation is mainly under the control of phosphorylation through the polarity kinase Pom1 s pathway including Cdr2 and Cdr1 10 11 12 13 At the G2 M transition Cdk1 is activated by Cdc25 through dephosphorylation of Tyr15 At the same time Wee1 is inactivated through phosphorylation at its C terminal catalytic domain by Nim1 Cdr1 12 Also the active MPF will promote its own activity by activating Cdc25 and inactivating Wee1 creating a positive feedback loop though this is not yet understood in detail 6 Higher eukaryotes regulate Wee1 via phosphorylation and degradation In higher eukaryotes Wee1 inactivation occurs both by phosphorylation and degradation 14 The protein complex nb 1 SCFb TrCP1 2 is an E3 ubiquitin ligase that functions in Wee1A ubiquitination The M phase kinases Polo like kinase Plk1 and Cdc2 phosphorylate two serine residues in Wee1A which are recognized by SCFb TrCP1 2 15 S cerevisiae homologue Swe1 In S cerevisiae cyclin dependent kinase Cdc28 Cdk1 homologue is phosphorylated by Swe1 Wee1 homologue and dephosphorylated by Mih1 Cdc25 homologue Nim1 Cdr1 homologue in S cerevisiae Hsl1 together with its related kinases Gin4 and Kcc4 localize Swe1 to the bud neck Bud neck associating kinases Cla4 and Cdc5 polo kinase homologue phosphorylate Swe1 at different stages of the cell cycle Swe1 is also phosphorylated by Clb2 Cdc28 which serves as a recognition for further phosphorylation by Cdc5 The S cerevisiae protein Swe1 is also regulated by degradation Swe1 is hyperphosphorylated by Clb2 Cdc28 and Cdc5 which may be a signal for ubiquitination and degradation by SCF E3 ubiquitin ligase complex as in higher eukaryotes 16 Role in cancer EditThe mitosis promoting factor MPF also regulates DNA damage induced apoptosis Negative regulation of MPF by WEE1 causes aberrant mitosis and thus resistance to DNA damage induced apoptosis Kruppel like factor 2 KLF2 negatively regulates human WEE1 thus increasing sensitivity to DNA damage induced apoptosis in cancer cells 17 Mutant phenotype EditWee1 acts as a dosage dependent inhibitor of mitosis 18 Thus the amount of Wee1 protein correlates with the size of the cells The fission yeast mutant wee1 also called wee1 divides at a significantly smaller cell size than wildtype cells Since Wee1 inhibits entry into mitosis its absence will lead to division at a premature stage and sub normal cell size Conversely when Wee1 expression is increased mitosis is delayed and cells grow to a large size before dividing See also EditWee1 like protein kinase Cell cycleNotes Edit b transducin repeat containing protein 1 2 b TrCP1 2 F box protein containing SKP1 Cul1 F box protein complexReferences Edit Nurse P December 2004 Wee beasties Nature 432 7017 557 Bibcode 2004Natur 432 557N doi 10 1038 432557a PMID 15577889 S2CID 29840746 Nurse P Thuriaux P November 1980 Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe Genetics 96 3 627 37 doi 10 1093 genetics 96 3 627 PMC 1214365 PMID 7262540 Den Haese GJ Walworth N Carr AM Gould KL 1995 The Wee1 protein kinase regulates T14 phosphorylation of fission yeast Cdc2 Mol Biol Cell 6 4 371 85 doi 10 1091 mbc 6 4 371 PMC 301198 PMID 7626804 Kim SY Ferrell JE Jr 23 March 2007 Substrate competition as a source of ultrasensitivity in the inactivation of Wee1 Cell 128 6 1133 45 doi 10 1016 j cell 2007 01 039 PMID 17382882 S2CID 14138576 Coleman TR Dunphy WG 1994 Cdc2 regulatory factors Current Opinion in Cell Biology 6 6 877 82 doi 10 1016 0955 0674 94 90060 4 PMID 7880537 a b c Kellogg DR 2003 Wee1 dependent mechanisms required for coordination of cell growth and cell division J Cell Sci 116 24 4883 90 doi 10 1242 jcs 00908 PMID 14625382 Rowley R Hudson J Young PG 1992 The wee1 protein kinase is required for radiation induced mitotic delay Nature 356 6367 353 5 Bibcode 1992Natur 356 353R doi 10 1038 356353a0 PMID 1549179 S2CID 4280074 Mahajan K Fang B Koomen JM Mahajan NP 2012 H2B Tyr37 phosphorylation suppresses expression of replication dependent core histone genes Nature Structural amp Molecular Biology 19 9 930 7 doi 10 1038 nsmb 2356 PMC 4533924 PMID 22885324 Mahajan K Mahajan NP 2013 WEE1 tyrosine kinase a novel epigenetic modifier Trends Genet 29 7 394 402 doi 10 1016 j tig 2013 02 003 PMC 3700603 PMID 23537585 Boddy MN Furnari B Mondesert O Russell P May 1998 Replication checkpoint enforced by kinases Cds1 and Chk1 Science 280 5365 909 12 Bibcode 1998Sci 280 909B doi 10 1126 science 280 5365 909 PMID 9572736 Wu L Russell P June 1993 Nim1 kinase promotes mitosis by inactivating Wee1 tyrosine kinase Nature 363 6431 738 41 Bibcode 1993Natur 363 738W doi 10 1038 363738a0 PMID 8515818 S2CID 4320080 a b Coleman TR Tang Z Dunphy WG March 1993 Negative regulation of the wee1 protein kinase by direct action of the nim1 cdr1 mitotic inducer Cell 72 6 919 29 doi 10 1016 0092 8674 93 90580 J PMID 7681363 S2CID 42256641 Tang Z Coleman TR Dunphy WG September 1993 Two distinct mechanisms for negative regulation of the Wee1 protein kinase EMBO J 12 9 3427 36 doi 10 1002 j 1460 2075 1993 tb06017 x PMC 413619 PMID 7504624 Watanabe N Broome M Hunter T May 1995 Regulation of the human WEE1Hu CDK tyrosine 15 kinase during the cell cycle EMBO J 14 9 1878 91 doi 10 1002 j 1460 2075 1995 tb07180 x PMC 398287 PMID 7743995 Watanabe N Arai H Nishihara Y et al March 2004 M phase kinases induce phospho dependent ubiquitination of somatic Wee1 by SCFbeta TrCP Proc Natl Acad Sci U S A 101 13 4419 24 Bibcode 2004PNAS 101 4419W doi 10 1073 pnas 0307700101 PMC 384762 PMID 15070733 Lee KS Asano S Park JE Sakchaisri K Erikson RL October 2005 Monitoring the cell cycle by multi kinase dependent regulation of Swe1 Wee1 in budding yeast Cell Cycle 4 10 1346 9 doi 10 4161 cc 4 10 2049 PMID 16123596 Wang F Zhu Y Huang Y et al June 2005 Transcriptional repression of WEE1 by Kruppel like factor 2 is involved in DNA damage induced apoptosis Oncogene 24 24 3875 85 doi 10 1038 sj onc 1208546 PMID 15735666 Russell P Nurse P May 1987 Negative regulation of mitosis by wee1 a gene encoding a protein kinase homolog Cell 49 4 559 67 doi 10 1016 0092 8674 87 90458 2 PMID 3032459 S2CID 42801276 External links EditDrosophila wee The Interactive Fly Portal Biology Retrieved from https en wikipedia org w index php title Wee1 amp oldid 1092075826, wikipedia, wiki, book, books, library,
