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Molecular and Cellular Biology, January 2003, p. 216-228, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.216-228.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Novel p27kip1 C-Terminal Scatter Domain Mediates Rac-Dependent Cell Migration Independent of Cell Cycle Arrest Functions

Sandra S. McAllister,1,2 Michelle Becker-Hapak,1,2 Giuseppe Pintucci,3 Michele Pagano,3 and Steven F. Dowdy1,4*

Howard Hughes Medical Institute,1 Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, California 92093-0686,4 Departments of Pathology and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110,2 Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 100163

Received 29 May 2002/ Returned for modification 26 June 2002/ Accepted 4 October 2002

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 p27kip1 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.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, University of California San Diego School of Medicine, La Jolla, CA 92093-0686. Phone: (858) 534-7772. Fax: (858) 534-7797. E-mail: sdowdy{at}ucsd.edu.

Molecular and Cellular Biology, January 2003, p. 216-228, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.216-228.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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