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© The Rockefeller University Press, 0021-9525/1999//389 $5.00
The Journal of Cell Biology, Volume 146, Number 2, , 1999 389-404

Original Article

Shc and Fak Differentially Regulate Cell Motility and Directionality Modulated by Pten



Jianguo Gua, Masahito Tamuraa, Roumen Pankova, Erik H.J. Danena, Takahisa Takinoa, Kazue Matsumotoa, and Kenneth M. Yamadaa

a Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4370
Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30, Room 421, 30 Convent Drive MSC 4370, Bethesda, MD 20892-4370.(301) 402-0897(301) 496-9124

ky4w{at}nih.gov

Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130Cas). We now report a novel pathway regulating random cell motility involving Shc and mitogen-activated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN- reconstituted U87-MG cells stimulated integrin- mediated MAP kinase activation and cell migration. Conversely, overexpression of dominant negative Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130Cas was directionally persistent and involved extensive organization of actin microfilaments and focal adhesions. In contrast, Shc or MEK1 induced a random type of motility associated with less actin cytoskeletal and focal adhesion organization. These results identify two distinct, additive pathways regulating cell migration that are downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration, whereas the other involves FAK, p130Cas, more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility. Integration of these pathways provides an intracellular mechanism for regulating the speed and the directionality of cell migration.

Key Words: Shc • focal adhesion kinase • integrin • cell migration • PTEN

© 1999 The Rockefeller University Press

1.used in this paper: Csk, COOH-terminal Src kinase; ERK, extracellular signal-related kinase; FAK, focal adhesion kinase; FRNK, dominant negative FAK truncation; GFP, green fluorescent protein; HA, hemagglutinin; MAP, mitogen-activated protein; MEK, MAP or ERK kinase; p130Cas, p130 Crk-associated substrate; PIP3, phosphatidylinositol 3,4,5-trisphosphate

The present address of J. Gu is Division of Protein Chemistry, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565, Japan. The present address of M. Tamura is Second Department of Internal Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555, Japan. The present address of E.H.J. Danen is Division of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.


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