Mechanisms in LPA-induced tumor cell migration: critical role of phosphorylated ERK.
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.
Stähle
Martina
M
Department of Pharmacology and Toxicology, University of Ulm, 89069 Ulm, Germany.
Veit
Christine
C
Bachfischer
Ulla
U
Schierling
Karina
K
Skripczynski
Bettina
B
Hall
Alan
A
Gierschik
Peter
P
Giehl
Klaudia
K
D000199:Actins / Q000378:metabolism; D002455:Cell Division; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D022001:Focal Adhesions / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein