The Cdk inhibitor p57(Kip2) controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics.
The cyclin-dependent kinase inhibitor p57(Kip2) gene has been suggested to be a tumor suppressor gene, being inactivated in various cancer types, linked to tumor progression and poor patient outcome. Here, we report that p57(Kip2) interacts with the actin cytoskeleton modifying enzyme, LIM-kinase 1 (LIMK-1) but not LIMK-2. This interaction enhances activity of LIMK-1, independently of its activator Rho-associated kinase. This resulted in an increased phosphorylation and consequent inactivation of the actin depolymerization factor, cofilin. In accordance, selective p57(Kip2) expression promotes actin stress fiber formation in cancer cells. Fluorescence recovery after photobleaching analysis of fluorescent-labeled actin further demonstrated that p57(Kip2) expression results in reduction of actin protein mobile fraction, which affects its turnover rate in cell. Finally, we present evidence that the p57(Kip2) control of LIMK-1 ultimately affects cell mobility negatively. Thus, in addition to its established function in control of proliferation and cell death, these results indicate that p57(Kip2) is critical in the regulation of actin cytoskeleton dynamic and by this means migration ability of cancer cells.
Vlachos
P
P
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institute, Stockholm, Sweden.
Joseph
B
B
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D016923:Cell Death / Q000235:genetics; D002465:Cell Movement; D002522:Chlorocebus aethiops; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*
D000199:Actins; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009363:Neoplasm Proteins; C515892:LIMK1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases