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Chek1

Protein FULL name:

serine/threonine-protein kinase Chk1 [Mus musculus].


Chek1 (Mus musculus) is product of expression of Chek1 gene.






FUNCTION: Required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. Recognizes the substrate consensus sequence [R-X-X- S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-171' and 'Thr-497' and phosphorylation of CDC25C creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-74', 'Ser-122', 'Ser-171', 'Ser-271' and 'Ser-284' promotes proteolysis of CDC25A. Inhibition of CDC25 activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Binds to and phosphorylates RAD51 at 'Thr-309', which may enhance the association of RAD51 with chromatin and promote DNA repair by homologous recombination. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may affect chromatin assembly during S phase or DNA repair. May also phosphorylate multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and enhances suppression of cellular proliferation (By similarity). Essential for early embryogenesis.

CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.

SUBUNIT: Interacts with BRCA1, CLSPN, FBXO6, PPM1D, RAD51, TIMELESS, XPO1/CRM1 and YWHAZ/14-3-3 zeta (By similarity).

INTERACTION: O14757:CHEK1 (xeno); NbExp=1; IntAct=EBI-2553137, EBI-974488;

SUBCELLULAR LOCATION: Nucleus (By similarity). Cytoplasm (By similarity). Cytoplasm, cytoskeleton, centrosome (By similarity). Note=Nuclear export is mediated at least in part by XPO1/CRM1. Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B (By similarity).

TISSUE SPECIFICITY: Found in all adult tissues tested. Elevated expression in testis, lung and spleen. 15.5 day old embryos show ubiquitous expression with strong expression in brain, liver, kidney, pancreas, intestine, thymus and lung.

DEVELOPMENTAL STAGE: In the testis, present in cells undergoing meiosis I. Not detected in peripheral cells in seminiferous tubules that are undergoing pre-meiotic DNA synthesis or in late condensing or mature sperm.

DOMAIN: The autoinhibitory region (AIR) inhibits the activity of the kinase domain (By similarity).

PTM: Phosphorylated by ATR in response to ultraviolet irradiation and inhibition of DNA replication. May also be phosphorylated by ATM in response to ionizing irradiation. ATM and ATR may phosphorylate both Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylated at Ser-280 by AKT1/PKB, which may promote mono and/or diubiquitination. May also be phosphorylated at undefined residues during mitotic arrest, which results in decreased activity.

PTM: The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination of activated form is required to insure that activated CHK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication (By similarity). Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion.

DISRUPTION PHENOTYPE: Mice die of apoptosis at the blastocyst stage.

MISCELLANEOUS: Haploinsufficient for the suppression of genomic instability and tumor progression.

SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.

SIMILARITY: Contains 1 protein kinase domain.

SEQUENCE CAUTION: Sequence=AAH37613.1; Type=Erroneous initiation;


NCBI GenPept GI number(s): 31542385
Species: Mus musculus

Links to other databases:

Database ID Link
Uniprot O35280 O35280
PFAM: - O35280 (Link - using uniprot id)
InterPro: - O35280 (Link - using uniprot id)
CATH: - -
SCOP: - -
PDB: - -


Protein sequence:
MAVPFVEDWDLVQTLGEGAYGEVQLAVNRITEEAVAVKIVDMKRAIDCPE
NIKKEICINKMLSHENVVKFYGHRREGHIQYLFLEYCSGGELFDRIEPDI
GMPEQDAQRFFHQLMAGVVYLHGIGITHRDIKPENLLLDERDNLKISDFG
LATVFRHNNRERLLNKMCGTLPYVAPELLKRKEFHAEPVDVWSCGIVLTA
MLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLALLHKILVETP
SARITIPDIKKDRWYNKPLNRGAKRPRATSGGMSESSSGFSKHIHSNLDF
SPVNNGSSEETVKFSSSQPEPRTGLSLWDTGPSNVDKLVQGISFSQPTCP
EHMLVNSQLLGTPGSSQNPWQRLVKRMTRFFTKLDADKSYQCLKETFEKL
GYQWKKSCMNQVTVSTTDRRNNKLIFKINLVEMDEKILVDFRLSKGDGLE
FKRHFLKIKGKLSDVVSSQKVWFPVT

Chek1 (Mus musculus) belongs to following protein families:
References:

Title Authors Journal
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ Science Sept. 5, 1997
Atm-dependent interactions of a mammalian chk1 homolog with meiotic chromosomes. Flaggs G, Plug AW, Dunks KM, Mundt KE, Ford JC, Quiggle MR, Taylor EM, Westphal CH, Ashley T, Hoekstra MF, Carr AM Curr Biol Dec. 1, 1997
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ Genes Dev June 15, 2000
Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice. Takai H, Tominaga K, Motoyama N, Minamishima YA, Nagahama H, Tsukiyama T, Ikeda K, Nakayama K, Nakanishi M, Nakayama K Genes Dev June 15, 2000
Chk1 is haploinsufficient for multiple functions critical to tumor suppression. Lam MH, Liu Q, Elledge SJ, Rosen JM Cancer Cell July 1, 2004
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J Genome Res Oct. 1, 2004
Lack of PTEN sequesters CHK1 and initiates genetic instability. Puc J, Keniry M, Li HS, Pandita TK, Choudhury AD, Memeo L, Mansukhani M, Murty VV, Gaciong Z, Meek SE, Piwnica-Worms H, Hibshoosh H, Parsons R Cancer Cell Jan. 1, 2005
The transcriptional landscape of the mammalian genome. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y Science Sept. 2, 2005
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ Science May 25, 2007


Last modification of this entry: Oct. 6, 2010.

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