Lysophosphatidic acid induces neuronal shape changes via a novel, receptor-mediated signaling pathway: similarity to thrombin action.
Lysophosphatidic acid (LPA) is a mitogenic phospholipid produced by certain activated cells and present in serum. LPA stimulates phospholipase C and inhibits adenylate cyclase in its target cells, apparently by activating a specific G-protein-coupled receptor. Here, we demonstrate that LPA causes transient rounding of N1E-115 and NG108-15 neuronal cells accompanied by growth cone collapse and retraction of neurites. The effect of LPA is concentration dependent, being half-maximal at 10-20 nM, and reversibly blocked by suramin, an LPA receptor antagonist. The morphological response to LPA is indistinguishable from that evoked by thrombin or a thrombin receptor-activating peptide (TRP) (K. Jalink and W. H. Moolenaar, J. Cell Biol., 118: 411-419, 1992); yet, LPA and thrombin appear to act through distinct receptors. LPA-induced shape changes, like those induced by thrombin and TRP, are driven by contraction of the cortical actin cytoskeleton and not attributable to prior phospholipid hydrolysis and Ca2+ mobilization nor to other classic second messenger systems. Instead, LPA- and TRP-induced shape changes are accompanied by a small but significant increase in p60src protein tyrosine kinase activity. Treatment of cells with pervanadate selectively inhibits LPA- and TRP-induced shape changes as well as p60src activation. These results indicate that, in N1E-115 and NG108-15 cells, LPA and TRP trigger neurite retraction and cell rounding through a novel, receptor-mediated signaling pathway, and they suggest that p60src may play a role in this pathway.
Jalink
K
K
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam.
Eichholtz
T
T
Postma
F R
FR
van Corven
E J
EJ
Moolenaar
W H
WH
D000199:Actins / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003599:Cytoskeleton / Q000737:chemistry / Q000502:physiology; D004789:Enzyme Activation; D008246:Lysophospholipids / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D018179:Receptors, Thrombin; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000199:Actins; D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D013917:Thrombin