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

• Published in: Journal of cell science Vol. 116; no. Pt 18; pp. 3835 - 3846
• Main Authors: Stähle, Martina, Veit, Christine, Bachfischer, Ulla, Schierling, Karina, Skripczynski, Bettina, Hall, Alan, Gierschik, Peter, Giehl, Klaudia
• Format: Journal Article
• Language: English
• Published: England 15.09.2003
• Subjects: Actins - metabolism; Cell Division; Cell Movement - drug effects; Cell Movement - physiology; Cytoskeleton - metabolism; Enzyme Activation; Focal Adhesions - metabolism; Genes, ras - physiology; Humans; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; Microscopy, Fluorescence; Mitogen-Activated Protein Kinases - metabolism; Neoplasm Metastasis; Neoplasms - pathology; Phosphorylation; rac GTP-Binding Proteins - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Lysophosphatidic Acid; rhoA GTP-Binding Protein - metabolism; Signal Transduction; Tumor Cells, Cultured
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.00679

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.