A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1.
The Cks/Suc1 proteins associate with CDK/cyclin complexes, but their precise function(s) is not well defined. Here we demonstrate that Cks1 directs the ubiquitin-mediated proteolysis of the CDK-bound substrate p27Kip1 by the protein ubiquitin ligase (E3) SCF(Skp2). Cks1 associates with the F box protein Skp2 and is essential for recognition of the p27Kip1 substrate for ubiquitination in vivo and in vitro. Using purified recombinant proteins, we reconstituted p27Kip1 ubiquitination activity and show that it is dependent on Cks1. CKS1-/- mice are abnormally small, and cells derived from them proliferate poorly, particularly under limiting mitogen conditions, possibly due to elevated levels of p27Kip1.
Spruck
C
C
The Scripps Research Institute, La Jolla, California 92037, USA.
Strohmaier
H
H
Watson
M
M
Smith
A P
AP
Ryan
A
A
Krek
T W
TW
Reed
S I
SI
D020816:Amino Acid Motifs; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002457:Cell Extracts; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005347:Fibroblasts; D017353:Gene Deletion; D020672:I-kappa B Proteins / Q000378:metabolism; D008025:Ligases / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D002457:Cell Extracts; D019927:Cyclin E; D020672:I-kappa B Proteins; D029702:Schizosaccharomyces pombe Proteins; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C117097:Csk1 protein, S pombe; D018844:Cyclin-Dependent Kinases; D008025:Ligases