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PMID: 12482975 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Novel p27(kip1) C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions.

Molecular and cellular biology ·Vol. 23 ·No. 1 ·2003-01-00 ·Pages 216-28

McAllister SS, Becker-Hapak M, Pintucci G, Pagano M, Dowdy SF

Abstract

Hepatocyte growth factor (HGF) signaling via its receptor, the proto-oncogene Met, alters cell proliferation and motility and has been associated with tumor metastasis. HGF treatment of HepG2 human hepatocellular carcinoma cells induces cell migration concomitant with increased levels of the p27(kip1) cyclin-cdk inhibitor. HGF signaling resulted in nuclear export of endogenous p27 to the cytoplasm, via Ser-10 phosphorylation, where it colocalized with F-actin. Introduction of transducible p27 protein (TATp27) was sufficient for actin cytoskeletal rearrangement and migration of HepG2 cells. TATp27 mutational analysis identified a novel p27 C-terminal domain required for cell migration, distinct from the N-terminal cyclin-cyclin-dependent kinase (cdk) binding domain. Loss or disruption of the p27 C-terminal domain abolished both actin rearrangement and cell migration. The cell-scattering activity of p27 occurred independently of its cell cycle arrest functions and required cytoplasmic localization of p27 via Ser-10 phosphorylation. Furthermore, Rac GTPase was necessary for p27-dependent migration but alone was insufficient for HepG2 cell migration. These results predicted a migration defect in p27-deficient cells. Indeed, p27-deficient primary fibroblasts failed to migrate, and reconstitution with TATp27 rescued the motility defect. These observations define a novel role for p27 in cell motility that is independent of its function in cell cycle inhibition.

MeSH Terms
Actins/metabolism,ultrastructure Amino Acid Sequence CDC2-CDC28 Kinases Carcinoma, Hepatocellular/drug therapy,metabolism,pathology Cell Cycle/drug effects,physiology Cell Cycle Proteins/drug effects,genetics,metabolism Cell Movement Cells, Cultured Cyclin A/metabolism Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor Proteins Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/metabolism Cytoplasm/metabolism Cytoskeleton/metabolism,ultrastructure Fibroblasts/cytology,metabolism Fungal Proteins/metabolism Hepatocyte Growth Factor/metabolism,pharmacology Humans Liver Neoplasms/drug therapy,metabolism,pathology Molecular Sequence Data Phosphorylation Protein Serine-Threonine Kinases/metabolism Proto-Oncogene Mas Recombinant Proteins/genetics,metabolism Repressor Proteins Saccharomyces cerevisiae Proteins Tumor Suppressor Proteins/drug effects,genetics,metabolism rac GTP-Binding Proteins/metabolism
Chemicals
Actins Cell Cycle Proteins Cyclin A Cyclin-Dependent Kinase Inhibitor Proteins FAR1 protein, S cerevisiae Fungal Proteins MAS1 protein, human Proto-Oncogene Mas Recombinant Proteins Repressor Proteins Saccharomyces cerevisiae Proteins Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 Hepatocyte Growth Factor Protein Serine-Threonine Kinases CDC2-CDC28 Kinases CDK2 protein, human Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases rac GTP-Binding Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
McAllister Sandra S
Howard Hughes Medical Institute, University of California San Diego School of Medicine, La Jolla 92093-0686, USA.
Becker-Hapak Michelle
Pintucci Giuseppe
Pagano Michele
Dowdy Steven F
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.1.216-228.2003
Published
2003-01-00
Pages
216-28
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC140659
Subset
IM
Grants
NIGMS NIH HHS · R01-GM57587 · United States
NIGMS NIH HHS · R01 GM057587 · United States
NCI NIH HHS · R01-CA76584 · United States
NCI NIH HHS · R01 CA096098 · United States
NCI NIH HHS · R01 CA076584 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.1.216-228.2003 PMC Full Text View journal details
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