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First published online 5 August 2003
doi: 10.1242/jcs.00679

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Journal of Cell Science 116, 3835-3846 (2003)
doi: 10.1242/jcs.00679

Research Article

Mechanisms in LPA-induced tumor cell migration: critical role of phosphorylated ERK

Martina Stähle1, Christine Veit1, Ulla Bachfischer1, Karina Schierling1, Bettina Skripczynski1, Alan Hall2, Peter Gierschik1 and Klaudia Giehl1,*

1 Department of Pharmacology and Toxicology, University of Ulm, 89069 Ulm, Germany
2 MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK

* Author for correspondence (e-mail: klaudia.giehl{at}medizin.uni-ulm.de)

Accepted 22 May 2003

Lysophosphatidic acid (LPA) is a serum-borne phospholipid with hormone and growth factor-like properties. LPA has been shown to modulate tumor cell invasion and malignant cell growth. Here, we report that two human pancreatic carcinoma cell lines, PANC-1 and BxPC-3, express functionally active LPA receptors coupled to pertussis toxin-sensitive Gi/o-proteins. In contrast to other cell types, LPA does not act as a mitogen, but is an efficacious stimulator of cell migration of these tumor cells. LPA-induced chemotaxis is markedly dependent on activation of PTX-sensitive heterotrimeric G-proteins, on activation of the small GTPases Ras, Rac and RhoA, and on GTPase-dependent activation of ERK. LPA-induced ERK activation results in a transient translocation of the phosphorylated ERK to newly forming focal contact sites at the leading edge of the migrating cells. Inhibition of ERK activation and its subsequent translocation impaired LPA-induced chemotaxis and LPA-induced actin reorganization. Thus, pancreatic tumor cell migration in response to LPA is essentially controlled by activation of a Gi/o-ERK pathway and requires the LPA-induced activation of Ras, Rac1 and RhoA.

Key words: LPA, Migration, Ras, Rho, ERK, Pancreatic carcinoma




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