Platelet-derived growth factor and fibronectin-stimulated migration are differentially regulated by the Rac and extracellular signal-regulated kinase pathways.
Directed cell migration is essential for a variety of important biological processes ranging from development and angiogenesis to metastasis. Ras plays a pivotal role in the signaling cascade that governs chemotaxis of fibroblasts toward platelet-derived growth factor-BB (PDGF-BB). Ras activates multiple downstream pathways, which include the extracellular signal-regulated kinase (ERK), Rac, and Ral signaling cascades. We therefore investigated the role of the Rac and ERK pathways in cell migration. We showed that migration of fibroblasts toward PDGF-BB is inhibited by expression of dominant negative Asn-17 Rac1. Blocking of the ERK pathway by either expression of dominant negative Ala-218/Ala-222-mitogen-activated protein kinase kinase (A218/A222-MEK1) or by a MEK-specific inhibitor did not inhibit migration toward PDGF-BB. In contrast, migration toward soluble fibronectin was suppressed by inhibition of the ERK pathway but not by Asn-17 Rac1 expression. These results indicate that directed cell migration mediated by different receptor classes in response to different ligands differentially utilizes the Rac and ERK pathways and suggest that Rac might play a critical role in pathological processes such as angiogenesis and metastasis.
Anand-Apte
B
B
Department of Surgery, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zetter
B R
BR
Viswanathan
A
A
Qiu
R G
RG
Chen
J
J
Ruggieri
R
R
Symons
M
M
D000818:Animals; D000077214:Becaplermin; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005353:Fibronectins / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D008246:Lysophospholipids / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D020744:rac GTP-Binding Proteins
D004791:Enzyme Inhibitors; D005353:Fibronectins; D005419:Flavonoids; D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D000431:Ethanol; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one