Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt.

Abstract

Axl is a receptor tyrosine kinase originally identified as a transforming gene product in human myeloid leukemia cells. Previously, we showed that Axl expression correlated with neointima formation in balloon-injured rat carotid, and that Axl expression was highly regulated by angiotensin II. In the present study we tested the mechanisms by which Axl regulates vascular smooth muscle cell (VSMC) growth focusing on its ability to inhibit apoptosis. Treatment of cultured rat aortic VSMC for 24 h with 0% serum resulted in 19.8 +/- 1.4% apoptotic cells. Treatment of VSMC with 100 ng/ml Gas6 (the putative ligand for Axl) decreased apoptosis to 8.9 +/- 0.7% (P = 0.002, N = 17) as compared to a decrease with 10% serum to 3.0 +/- 0.2% (P = 0.001, N = 17). The ability of Gas6 to prevent apoptosis required both Gas6 binding to Axl and Axl kinase activity since treatment with a soluble, competitive Axl extracellular domain protein or transfection of a kinase inactive mutant (Axl-K567R) completely prevented the anti-apoptotic effect. Prevention of apoptosis by Gas6-Axl required activation of phosphatidyl inositol 3-kinase (PI3K) as shown by treatment with LY294002 or transfection of an Axl deletion mutant that does not bind PI3K (Axl- triangle up PI3K). There was no significant role for ERK1/2 in the anti-apoptotic effects of Gas6-Axl since ERK1/2 activity was maintained in cells transfected with Axl- triangle up PI3K and Axl-K567R. These findings establish the Gas6-Axl-PI3K-Akt pathway as an anti-apoptotic mechanism for VSMC that may be important in the response to vascular injury.

• Authors: Matthew G Melaragno, Megan E Cavet, Chen Yan, Lung-Kuo Tai, Zheng-Gen Jin, Judith Haendeler, Bradford C Berk
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 37 Issue 4 Pg. 881-7 (Oct 2004) ISSN: 0022-2828 [Print] England
• PMID: 15380678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chromones
• Intercellular Signaling Peptides and Proteins
• Morpholines
• Oncogene Proteins
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• growth arrest-specific protein 6
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Receptor Protein-Tyrosine Kinases
• Akt1 protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Axl Receptor Tyrosine Kinase

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cells, Cultured
• Chromones (pharmacology)
• Intercellular Signaling Peptides and Proteins (pharmacology, physiology)
• Morpholines (pharmacology)
• Muscle, Smooth, Vascular (cytology, physiology)
• Myocytes, Smooth Muscle (physiology)
• Oncogene Proteins (genetics, pharmacology, physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Serine-Threonine Kinases (physiology)
• Proto-Oncogene Proteins (physiology)
• Proto-Oncogene Proteins c-akt
• Pulmonary Artery (cytology)
• Rats
• Receptor Protein-Tyrosine Kinases (genetics, pharmacology, physiology)
• Sequence Deletion (genetics)
• Signal Transduction (physiology)
• Axl Receptor Tyrosine Kinase