Scientific Background: KIP1 (cyclin-dependent kinase inhibitor 1B) is a kinesin-related motor protein required for mitotic spindle assembly and chromosome segregation (1). Many tumorigenic processes modulate cell-cycle progression by regulating the levels of the cyclin-dependent kinase inhibitor KIP1. KIP1 binds to and inhibits cyclinE-Cdk2 complex, cyclinA-CDK2 and cyclinD1-CDK4 (2). The phosphorylation- and ubiquitination-dependent proteolysis of KIP1 is implicated in control of the G1-S transition in the cell cycle. KIP1 is critical for retinoblastoma protein (Rb)-induced cellular proliferative senescence.
2. Carrano,A C. et al: SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat. Cell Biol. 1999; 1, 193-199
NCBI and Uniprot Product Information
NCBI Description
This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. 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. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. [provided by RefSeq, Jul 2008]
Uniprot Description
Function: Important regulator of cell cycle progression. Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry. Ref.7 Ref.11 Ref.17 Ref.22 Ref.28
Subunit structure: Forms a ternary compex with CCNE1/CDK2/CDKN1B. Interacts directly with CCNE1; the interaction is inhibited by CDK2-dependent phosphorylation on Thr-187. Interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to CDKN1B degradation. Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated CDKN1B. Interacts with CCND1 and SNX6
By similarity. Interacts (Thr-198-phosphorylated form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm. Interacts with AKT1 and LYN; the interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Interacts (unphosphorylated form) with CDK2. Forms a ternary complex, cyclin D/CDK4/CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction is required for cyclin D/CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. Interacts with GRB2. Interacts with PIM1. Identified in a complex with SKP1, SKP2 and CKS1B. Interacts with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest. Interacts also with CDK1. Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.21 Ref.22 Ref.28
Subcellular location: Nucleus. Cytoplasm. Endosome
By similarity. Note: Nuclear and cytoplasmic in quiescent cells. AKT- or RSK-mediated phosphorylation on Thr-198, binds 14-3-3, translocates to the cytoplasm and promotes cell cycle progression. Mitogen-activated UHMK1 phosphorylation on Ser-10 also results in translocation to the cytoplasm and cell cycle progression. Phosphorylation on Ser-10 facilitates nuclear export. Translocates to the nucleus on phosphorylation of Tyr-88 and Tyr-89. Colocalizes at the endosome with SNX6; this leads to lysosomal degradation
By similarity. Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.16
Tissue specificity: Expressed in all tissues tested. Highest levels in skeletal muscle, lowest in liver and kidney.
Induction: Maximal levels in quiescence cells and early G1. Levels decrease after mitogen stimulation as cells progress toward S-phase. Ref.28
Domain: A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.
Post-translational modification: Phosphorylated; phosphorylation occurs on serine, threonine and tyrosine residues. Phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G(0)-G1 phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to protein ubiquitination and proteasomal degradation. Tyrosine 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 and Tyr-89 has no effect on binding CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.16 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 Ref.27 Ref.28Ubiquitinated; in the cytoplasm by the KPC complex (composed of RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a TRIM21-containing SCF(SKP2)-like complex; leads to its degradation. Ref.6 Ref.18 Ref.27Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation
By similarity.
Involvement in disease: Multiple endocrine neoplasia 4 (MEN4) [MIM:610755]: Multiple endocrine neoplasia (MEN) syndromes are inherited cancer syndromes of the thyroid. MEN4 is a MEN-like syndrome with a phenotypic overlap of both MEN1 and MEN2.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.19
Miscellaneous: Decreased levels of p27Kip1, mainly due to proteasomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.
Sequence similarities: Belongs to the CDI family.
Research Articles on p27KIP1
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Product Notes
The p27KIP1 cdkn1b (Catalog #AAA515403) is a Recombinant Protein produced from E Coli and is intended for research purposes only. The product is available for immediate purchase. The tag for this protein is GST tag!!Expression System||E.coli!!Source Note||Recombinant full-length human p27KIP1 was expressed in E. coli cells. AAA Biotech's p27KIP1 can be used in a range of immunoassay formats including, but not limited to, Kinase Assay, Western Blot (WB). Researchers should empirically determine the suitability of the p27KIP1 cdkn1b for an application not listed in the data sheet. Researchers commonly develop new applications and it is an integral, important part of the investigative research process. It is sometimes possible for the material contained within the vial of "p27KIP1, Recombinant Protein" to become dispersed throughout the inside of the vial, particularly around the seal of said vial, during shipment and storage. We always suggest centrifuging these vials to consolidate all of the liquid away from the lid and to the bottom of the vial prior to opening. Please be advised that certain products may require dry ice for shipping and that, if this is the case, an additional dry ice fee may also be required.Precautions
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