p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus.
p57Kip2 is the only cyclin-dependent kinase (Cdk) inhibitor shown to be essential for mouse embryogenesis. The fact suggests that p57 has a specific role that cannot be compensated by other Cdk inhibitors. LIM-kinase 1 (LIMK-1) is a downstream effector of the Rho family of GTPases that phosphorylates and inactivates an actin depolymerization factor, cofilin, to induce the formation of actin fiber. Here we demonstrate that p57 regulates actin dynamics by binding and translocating LIMK-1 from the cytoplasm into the nucleus, which in turn results in a reorganization of actin fiber. The central region of p57, a unique feature among the Cdk inhibitors, and the N-terminal region of LIMK-1, which contains the LIM domains were essential for the interaction. Expression of p57, but not p27Kip1 or a p57 mutant, with a deletion in the central region was shown to induce marked reorganization of actin filament and a translocation of LIMK-1. Our findings indicate p57 may act as a key regulator in embryogenesis by bearing two distinct functions, the regulation of cell cycle through binding to Cdks and the regulation of actin dynamics through binding to LIMK-1, both of which should be important in developmental procedure.
Yokoo
Tomotaka
T
Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Toyoshima
Hideo
H
Miura
Mitsuhiro
M
Wang
Yuhui
Y
Iida
Kaoruko Tada
KT
Suzuki
Hiroaki
H
Sone
Hirohito
H
Shimano
Hitoshi
H
Gotoda
Takanari
T
Nishimori
Shigeki
S
Tanaka
Keiji
K
Yamada
Nobuhiro
N
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002477:Cells; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015723:Gene Library; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D054461:Lim Kinases; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D000199:Actins; C493964:CDKN1C protein, human; C493961:Cdkn1b protein, mouse; C493965:Cdkn1c protein, mouse; D018797:Cell Cycle Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse