Excess early signaling activity inhibits cellular chemotaxis toward PDGF-BB.
Chemotaxis, directed migration toward a gradient of a soluble substance, requires a cell to spatially distinguish the concentration of a chemoattractant at one end relative to its opposite end. Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant. In the current study, we attempted to interfere with PDGF-BB mediated chemotaxis by abnormal expression of potential early components of the signaling cascade. We find that expression of the PDGF homolog v-Sis prevents cellular migration toward PDGF-BB, indicating that autocrine production of a PDGF receptor ligand will prevent the chemotactic response to exogenously added ligand. In addition, while it is known that PDGF receptor mutants incapable of activating tyrosine kinase activity cannot transduce a signal for mitogenesis or chemotaxis, the effects of excess tyrosine kinase activity on PDGF mediated chemotaxis have not been tested. We demonstrate that cells expressing constitutively active tyrosine kinase genes such as v-fms, v-fes, or v-src fail to migrate toward PDGF-BB whereas expression of the serine/threonine kinase v-mos does not block the chemotactic response. The results demonstrate that chemotaxis may be prevented by excess production of either ligand, receptor activity, or downstream signaling molecule. In addition, our results show that the signals that mediate chemotaxis are separable from those that regulate unstimulated random motility in the same cells.
Kundra
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Program in Biological and Biomedical Sciences, Harvard Medical School, Children's Hospital, Boston, Massachusetts.
Soker
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Zetter
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D016475:3T3 Cells; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement; D002633:Chemotaxis; D051379:Mice; D016281:Oncogene Protein gp140(v-fms) / Q000378:metabolism; D020575:Oncogene Proteins v-sis; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051578:Proto-Oncogene Proteins c-fes; D017231:Proto-Oncogene Proteins c-mos / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases
D016281:Oncogene Protein gp140(v-fms); D020575:Oncogene Proteins v-sis; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C496646:Fes protein, mouse; D051578:Proto-Oncogene Proteins c-fes; D019061:src-Family Kinases; D017231:Proto-Oncogene Proteins c-mos