CKS1B explained

Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.^{[1] [2]}

Function

The CKS1B protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function. The CKS1B mRNA is found to be expressed in different patterns through the cell cycle in HeLa cells, which reflects a specialized role for the encoded protein.^[2]

CKS1B and CKS2 proteins have demonstrated principal roles in cell cycle regulation. Defined originally as suppressors of mutations in both fission and budding yeast Cdk1 genes, Cks molecules interact with Cdk1, Cdk2 and Cdk3. These Cdk-dependent enzyme complexes in cell cycle regulation frequently consist of Cdk molecules bound to a catalytic Cdk subunit, i.e. Cks and a regulatory cyclin subunit, such as a G1 cyclin, controlling Cdk function by directing cyclin-cdk complex activity toward specific and significant substrates. Malfunctions of cdk-dependent associations lead to defects into the entry of mitosis for cells.^[3]

Cks1 in the Cdk-independent pathway involves the recognition of substrates p27^Kip1 and p21^cip1 by directly associating with E3 SCF^Skp2 when stimulated by certain mitogenic signals, such as TGF-β.^[4]

Clinical significance

Cks1-depleted breast cancer cells not only exhibit slowed G(1) progression, but also accumulate in G(2)-M due to blocked mitotic entry. Cdk1 expression, which is crucial for M phase entry, is drastically diminished by Cks1 depletion, and that restoration of cdk1 reduces G(2)-M accumulation in Cks1-depleted cells.^[5]

Interactions

CKS1B has been shown to interact with SKP2^{[6] [7] [8] [9]} and CDKN1B.^{[6] [7]}

Further reading

• Arvai AS, Bourne Y, Hickey MJ, Tainer JA . Crystal structure of the human cell cycle protein CksHs1: single domain fold with similarity to kinase N-lobe domain. . J. Mol. Biol. . 249 . 5 . 835–42 . 1995 . 7791211 . 10.1006/jmbi.1995.0341 .
• Bourne Y, Watson MH, Hickey MJ . Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1. . Cell . 84 . 6 . 863–74 . 1996 . 8601310 . 10.1016/S0092-8674(00)81065-X . 854793 . etal. free .
• Demetrick DJ, Zhang H, Beach DH . Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. . Cytogenet. Cell Genet. . 73 . 3 . 250–4 . 1996 . 8697818 . 10.1159/000134349 .
• Ganoth D, Bornstein G, Ko TK . The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27. . Nat. Cell Biol. . 3 . 3 . 321–4 . 2001 . 11231585 . 10.1038/35060126 . 9638655 . etal.
• Sitry D, Seeliger MA, Ko TK . Three different binding sites of Cks1 are required for p27-ubiquitin ligation. . J. Biol. Chem. . 277 . 44 . 42233–40 . 2003 . 12140288 . 10.1074/jbc.M205254200 . etal. free .
• Seeliger MA, Breward SE, Itzhaki LS . Weak cooperativity in the core causes a switch in folding mechanism between two proteins of the cks family. . J. Mol. Biol. . 325 . 1 . 189–99 . 2003 . 12473461 . 10.1016/S0022-2836(02)01202-0 .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Xu K, Belunis C, Chu W . Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase. . Biochem. J. . 371 . Pt 3 . 957–64 . 2003 . 12529174 . 10.1042/BJ20021722 . 1223319 . etal.
• Wang W, Ungermannova D, Chen L, Liu X . A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1. . J. Biol. Chem. . 278 . 34 . 32390–6 . 2003 . 12813041 . 10.1074/jbc.M305241200 . free .
• Bashir T, Dorrello NV, Amador V . Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. . Nature . 428 . 6979 . 190–3 . 2004 . 15014502 . 10.1038/nature02330 . 4401971 . etal.
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Kitajima S, Kudo Y, Ogawa I . Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. . Am. J. Pathol. . 165 . 6 . 2147–55 . 2005 . 15579456 . 10.1016/S0002-9440(10)63264-6. 1618711 . etal.
• Seeliger MA, Spichty M, Kelly SE . Role of conformational heterogeneity in domain swapping and adapter function of the Cks proteins. . J. Biol. Chem. . 280 . 34 . 30448–59 . 2005 . 15772084 . 10.1074/jbc.M501450200 . etal. free .
• Slotky M, Shapira M, Ben-Izhak O . The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. . Breast Cancer Res. . 7 . 5 . R737–44 . 2006 . 16168119 . 10.1186/bcr1278 . 1242136 . etal . free .
• Shaughnessy J . Amplification and overexpression of CKS1B at chromosome band 1q21 is associated with reduced levels of p27Kip1 and an aggressive clinical course in multiple myeloma. . Hematology . 10 Suppl 1 . 4. 117–26 . 2006 . 16188652 . 10.1080/10245330512331390140 . 16583295 .
• Rual JF, Venkatesan K, Hao T . Towards a proteome-scale map of the human protein-protein interaction network. . Nature . 437 . 7062 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 . etal.
• Hao B, Zheng N, Schulman BA . Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. . Mol. Cell . 20 . 1 . 9–19 . 2005 . 16209941 . 10.1016/j.molcel.2005.09.003 . etal. free .
• Bhatt KV, Hu R, Spofford LS, Aplin AE . Mutant B-RAF signaling and cyclin D1 regulate Cks1/S-phase kinase-associated protein 2-mediated degradation of p27Kip1 in human melanoma cells. . Oncogene . 26 . 7 . 1056–66 . 2007 . 16924241 . 10.1038/sj.onc.1209861 . free .
• Yao ZP, Zhou M, Kelly SE . Activation of ubiquitin ligase SCF(Skp2) by Cks1: insights from hydrogen exchange mass spectrometry. . J. Mol. Biol. . 363 . 3 . 673–86 . 2006 . 16979657 . 10.1016/j.jmb.2006.08.032 . etal.

Notes and References

1. Richardson HE, Stueland CS, Thomas J, Russell P, Reed SI . Human cDNAs encoding homologs of the small p34Cdc28/Cdc2-associated protein of Saccharomyces cerevisiae and Schizosaccharomyces pombe . Genes Dev . 4 . 8 . 1332–44 . Dec 1990 . 2227411 . 10.1101/gad.4.8.1332 . free .
2. Web site: Entrez Gene: CKS1B CDC28 protein kinase regulatory subunit 1B.
3. Harper, J.W. 2001. Protein destruction: Adapting roles for Cks proteins. Cur Biol. 11: R431–R435
4. Xu, K., Belunis, C., et al. 2003. Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase. Biochem J. 371: 957–964.
5. Westbrook L, Manuvakhova M, Kern FG, Estes NR, Ramanathan HN, Thottassery JV . Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells . Cancer Res. . 67 . 23 . 11393–401 . December 2007 . 18056467 . 10.1158/0008-5472.CAN-06-4173 . free .
6. Wang W, Ungermannova D, Chen L, Liu X . A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1 . J. Biol. Chem. . 278 . 34 . 32390–6 . August 2003 . 12813041 . 10.1074/jbc.M305241200 . free .
7. Sitry D, Seeliger MA, Ko TK, Ganoth D, Breward SE, Itzhaki LS, Pagano M, Hershko A . Three different binding sites of Cks1 are required for p27-ubiquitin ligation . J. Biol. Chem. . 277 . 44 . 42233–40 . November 2002 . 12140288 . 10.1074/jbc.M205254200 . free .
8. Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A . The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27 . Nat. Cell Biol. . 3 . 3 . 321–4 . March 2001 . 11231585 . 10.1038/35060126 . 9638655 .
9. Calvisi DF, Pinna F, Meloni F, Ladu S, Pellegrino R, Sini M, Daino L, Simile MM, De Miglio MR, Virdis P, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM . Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma . Cancer Res. . 68 . 11 . 4192–200 . June 2008 . 18519678 . 10.1158/0008-5472.CAN-07-6157 . free .