Nuclear translocation of LIM kinase mediates Rho-Rho kinase regulation of cyclin D1 expression.
We previously reported that the Rho-Rho kinase pathway controls cyclin D1 expression by preventing its early G1 phase induction in response to Rac and/or Cdc42, thus increasing its dependence on ERK signaling and actin stress fiber formation. We now show that the Rho kinase effector LIM kinase is responsible for this effect. Surprisingly, inhibition of Rac-dependent cyclin D1 expression by LIM kinase is independent of both cofilin phosphorylation and actin polymerization. Instead, specific mutation of its nuclear localization and export sequences showed that LIM kinase acts in the nucleus to suppress Rac/Cdc42-dependent cyclin D1 expression. Our results therefore describe an unexpected role for LIM kinase that requires nuclear translocation. The effect of nuclear LIM kinase on cyclin D1 expression ultimately regulates the duration of G1 phase and the degree to which G1 phase progression depends on actin stress fiber formation and imposition of cellular tension.
Roovers
Kristin
K
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. rka@pharm.med.upenn.edu
Klein
Eric A
EA
Castagnino
Paola
P
Assoian
Richard K
RK
D051339:Actin Depolymerizing Factors; D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D054461:Lim Kinases; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
D051339:Actin Depolymerizing Factors; D000199:Actins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D016596:Vinculin; D019938:Cyclin D1; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins