GAS6 induces Axl-mediated chemotaxis of vascular smooth muscle cells.
Atherosclerosis and arterial restenosis are disease processes involving the accumulation of vascular smooth muscle cells following vascular injury. Key events leading to these processes are migration and proliferation of these cells. Here, we demonstrate that GAS6, encoded by the growth arrest-specific gene 6, induces a directed migration (chemotaxis) of both rat and human primary vascular smooth muscle cells while showing only marginal mitogenic potential in human vascular smooth muscle cells. GAS6 stimulation induces Axl autophosphorylation in human vascular smooth muscle cells, indicating that specific GAS6-Axl interactions may be associated with GAS6-directed chemotaxis. To test this hypothesis, vascular smooth muscle cells overexpressing Axl were generated by gene transfer and assessed for their ability to migrate along a GAS6 gradient. These Axl overexpressors exhibited 2-5-fold increased sensitivity to GAS6-induced chemotaxis. Furthermore, vascular smooth muscle cells expressing the kinase dead mutant of Axl or exposure to the soluble Axl extracellular domain showed attenuated GAS6-induced migration. Taken together, these results suggest that GAS6 is a novel chemoattractant that induces Axl-mediated migration of vascular smooth muscle cells. The separation of mitogenesis from migration provided by this study may enhance the molecular dissection of cell migration in vascular damage.
Fridell
Y W
YW
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.
Villa
J
J
Attar
E C
EC
Liu
E T
ET
D000818:Animals; D002633:Chemotaxis / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D015513:Oncogene Proteins / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6