Cell Adhesion to Phosphatidylserine Mediated by a Product of Growth Arrest-specific Gene 6

Toru Nakano,Yoshikazu Ishimoto,Junji Kishino,Masato Umeda,Keizo Inoue,Kyoko Nagata,Kazumasa Ohashi,Kensaku Mizuno,Hitoshi Arita

doi:10.1074/jbc.272.47.29411

Abstract

Gas6, a product of a growth arrest-specific gene 6, potentiates proliferation of vascular smooth muscle cells and prevents cell death of vascular smooth muscle cells. It has been also demonstrated that Gas6 is a ligand of receptor tyrosine kinases Axl, Sky, and Mer. Gas6 contains gamma-carboxyglutamic acid residues, which are found in some blood coagulation factors and mediate the interaction of the coagulation factors with negatively charged phospholipid. In this study, we clarified that Gas6 specifically bound to phosphatidylserine and the binding was dependent on Ca2+ and gamma-carboxyglutamic acid residues. Furthermore, we found that U937 cells, which express Gas6 receptor on their surfaces, adhered to phosphatidylserine-coated enzyme-linked immunosorbent assay (ELISA) plate only in the presence of Gas6 and Ca2+. U937 cells also bound to ELISA plate coated with phosphatidylinositol, but the binding was independent of Gas6 and Ca2+. On the other hand, U937 cells did not adhere to phosphatidylcholine- or phosphatidylethanolamine-coated ELISA plate even in the presence of Gas6 and Ca2+. These findings suggest that Gas6 may play a role in recognition of cells exposing phosphatidylserine on their surfaces by phagocytic cells, which is supposed to be one of the mechanisms for clearing dying cells.

Highlights

Gas6 was initially identified as a product of a gene whose expression in fibroblasts increased during the growth-arrested state, its biological activity was unclear [1]
1 The abbreviations used are: vascular smooth muscle cells (VSMCs), vascular smooth muscle cell; VSMC proliferation mediated by Ca2ϩ-mobilizing receptors [2]
Another biological activity of Gas6 is the prevention of cell death of VSMCs and fibroblasts [3, 4]

Summary

Introduction

Gas6 was initially identified as a product of a gene whose expression in fibroblasts increased during the growth-arrested state, its biological activity was unclear [1]. The function of the Gla domain of protein S is thought to be mediation of its Ca2ϩ-dependent binding to negatively charged phospholipids, which is important for the biological activity of protein S [18]. The specific binding of Gas6 to its receptor on cell membrane has been shown to be dependent on Ca2ϩ [19], suggesting that interaction of the Gla domain with Ca2ϩ is important for the receptor binding.

Results

Conclusion