CKS1B

Last updated
CKS1B
Protein CKS1B PDB 1buh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CKS1B , CKS1, PNAS-16, PNAS-18, ckshs1, CDC28 protein kinase regulatory subunit 1B
External IDs OMIM: 116900 MGI: 1889208 HomoloGene: 123798 GeneCards: CKS1B
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001826

NM_016904

RefSeq (protein)

NP_001817

NP_058600

Location (UCSC) Chr 1: 154.97 – 154.98 Mb n/a
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene. [4] [5]

Contents

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. [5]

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. [6]

Cks1 in the Cdk-independent pathway involves the recognition of substrates p27Kip1 and p21cip1 by directly associating with E3 SCFSkp2 when stimulated by certainmitogenic signals, such as TGF-β. [7]

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. [8]

Interactions

CKS1B has been shown to interact with SKP2 [9] [10] [11] [12] and CDKN1B. [9] [10]

Related Research Articles

p21

p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

SCF complex

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

F-box protein Protein containing at least one F-box domain

F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.

Cyclin-dependent kinase 2

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

Cyclin-dependent kinase 4 Human protein

Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

Cyclin-dependent kinase 9

Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.

CDKN1B

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

Cyclin T1

Cyclin-T1 is a protein that in humans is encoded by the CCNT1 gene.

SKP2

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.

CUL1

Cullin 1, also known as CUL1, is a human protein and gene from cullin family. This protein plays an important role in protein degradation and protein ubiquitination.

RBX1

RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.

Cyclin A2

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.

FBXW7

F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.

CDC34

CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.

RNF7

RING-box protein 2 is a protein that in humans is encoded by the RNF7 gene.

CKS2

Cyclin-dependent kinases regulatory subunit 2 is a protein that in humans is encoded by the CKS2 gene.

CCNF

G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.

Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb complexes in the budding yeast Saccharomyces cerevisiae. Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase entry. Multisite phosphorylation of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry.

S-phase kinase-associated protein 1

S-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000173207 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. Richardson HE, Stueland CS, Thomas J, Russell P, Reed SI (Dec 1990). "Human cDNAs encoding homologs of the small p34Cdc28/Cdc2-associated protein of Saccharomyces cerevisiae and Schizosaccharomyces pombe". Genes Dev. 4 (8): 1332–44. doi: 10.1101/gad.4.8.1332 . PMID   2227411.
  5. 1 2 "Entrez Gene: CKS1B CDC28 protein kinase regulatory subunit 1B".
  6. Harper, J.W. 2001. Protein destruction: Adapting roles for Cks proteins. Cur Biol. 11: R431–R435
  7. 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.
  8. Westbrook L, Manuvakhova M, Kern FG, Estes NR, Ramanathan HN, Thottassery JV (December 2007). "Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells". Cancer Res. 67 (23): 11393–401. doi: 10.1158/0008-5472.CAN-06-4173 . PMID   18056467.
  9. 1 2 Wang W, Ungermannova D, Chen L, Liu X (August 2003). "A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1". J. Biol. Chem. 278 (34): 32390–6. doi: 10.1074/jbc.M305241200 . PMID   12813041.
  10. 1 2 Sitry D, Seeliger MA, Ko TK, Ganoth D, Breward SE, Itzhaki LS, Pagano M, Hershko A (November 2002). "Three different binding sites of Cks1 are required for p27-ubiquitin ligation". J. Biol. Chem. 277 (44): 42233–40. doi: 10.1074/jbc.M205254200 . PMID   12140288.
  11. Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A (March 2001). "The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27". Nat. Cell Biol. 3 (3): 321–4. doi:10.1038/35060126. PMID   11231585. S2CID   9638655.
  12. 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 (June 2008). "Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma". Cancer Res. 68 (11): 4192–200. doi: 10.1158/0008-5472.CAN-07-6157 . PMID   18519678.

Further reading