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p27KIP1; cyclin-dependent kinase inhibitor 1B; cyclin-dependent kinase inhibitor p27 (CDKN1B, KIP1)

Function: - regulator of cell cycle progression - involved in G1 arrest - potent inhibitor of cyclin E-CDK2 & cyclin A-CDK2 complexes - positive regulator of cyclin D-dependent kinases such as CDK4 - regulated by phosphorylation & degradation events - interacts with NUP50; the interaction leads to nuclear import & degradation of phosphorylated p27KIP1 - interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to p27KIP degradation - interacts with SPDYA in the SPDYA/CDK2/p27kip1 complex - interacts (Thr-198 phosphorylated-form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE & YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm - interacts with AKT1, LYN & UHMK1; the interactions lead to cytoplasmic mislocation, phosphorylation of p27kip1 & inhibition of cell cycle arrest - interacts (unphosphorylated form) with CDK2 - interacts (phosphorylated on Tyr-88 & Tyr-89) with CDK4; the interaction induces nuclear translocation - interacts with GRB2 phosphorylated - phosphorylation occurs on Ser, Thr & Tyr - phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G0-G1 phase & leads to protein stability - phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC & in certain cancer cell lines - the phosphorylated form found in the cytoplasm is inactive - phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins - phosphorylation on Thr-187, by CDK2 leads to protein ubiquitination & proteasomal degradation; Tyr phosphorylation promotes this process - phosphorylation by PKB/AKT1 can be suppressed by LY294002, an inhibitor of the catalytic subunit of PI3K - phosphorylation on Tyr-88 & Tyr-89 has no effect on binding CDK2, but is required for binding CDK4 - dephosphorylated on Tyr by G-CSF - ubiquitinated; in cytoplasm by the KPC1/KPC2 complex &, in nucleus, by SCF/SKP2 (requires prior phosphorylation on Thr-187) - p27KIP1 & related p21WAF1/CIP1 preferentially inhibit CDK2 & CDK4-cyclin complexes [3] - overexpression prevents entry into S phase - p27kip1 inhibits Rb phorphorylation by cyclin E-Cdk2, cyclin A-Cdk2 & cyclin D2-Cdk4 - p27KIP1 has a region of sequence similarity to p21cip1/waf1 (pic1 protein) & is implicated in the G1 phase arrest by TGF beta, cell-cell contact, agents that elevate cAMP & the growth inhibitory drug rapamycin [4] - AKT- or RSK-mediated phosphorylation on Thr-198, binds 14-3-3, translocates to the cytoplasm & promotes cell cycle progression - mitogen-activated UHMK1 phosphorylation on Ser-10 also results in translocation to the cytoplasm & cell cycle progression - phosphorylation on Ser-10 facilitates nuclear export - translocates to the nucleus on phosphorylation of Tyr-88 & Tyr-89 Structure: - peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity - belongs to the CDI family Compartment: - nucleus, cytoplasm - nuclear & cytoplasmic in quiescent cells Expression: - expressed in all tissues tested - highest levels in skeletal muscle, lowest in liver & kidney - maximal levels in quiescence cells & early G1 phase - levels decrease after mitogen stimulation as cells progress toward S-phase Pathology: - defects in CDKN1B are the cause of multiple endocrine neoplasia 4 (MEN4) - decreased levels of p27Kip1, mainly due to proteosomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid & prostate Laboratory: - CDKN1B gene mutation

Interactions

molecular events

General

anti-oncoprotein (tumor suppressor protein) cyclin-dependent kinase inhibitor (CDKI, CDKN) nuclear protein phosphoprotein

Properties

COMPARTMENT: cytoplasm cell nucleus INHIBITS: protein kinase SIZE: entity length = 198 aa MW = 22 kD MOTIF: Ser phosphorylation site {S10} Tyr phosphorylation site {Y74} Tyr phosphorylation site {Y88} Tyr phosphorylation site {Y89} Ser phosphorylation site {S140} nuclear translocation signal {153-169} MOTIF: Thr phosphorylation site {T157} Thr phosphorylation site {T187} Thr phosphorylation site {T198}

Database Correlations

OMIM correlations UniProt P46527 Pfam PF02234 Entrez Gene 1027 Kegg hsa:1027

References

  1. Polyak K et al Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994 Jul 15;78(1):59-66. PMID: 8033212
  2. Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67-74. PMID: 8033213
  3. Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131-4. Review. PMID: 7877684
  4. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: 7677168
  5. Entrez Gene :accession 1027
  6. UniProt :accession P46527
  7. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN1BID116.html

Component-of

molecular complex