Gas6 gains entry into the coagulation cascade.

phohistiocytosis in syntaxin-11 deficient mice: T-cell exhaustion limits fatal disease. essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Linkage of fa-milial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syn-taxin 11. A, et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocyto-sis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.mophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Gas6 gains entry into the coagulation cascade COLUMBIA In this issue of Blood, Robins and colleagues provide new insights into how Gas6 promotes thrombosis through contributions from platelets and from the vascular wall. By showing that Gas6 up-regulates the initiator of coagulation, tissue factor, in the endothelium, these studies may yield new and safer treatments for throm-botic disease. 1 G as6 is a vitamin K dependent (VKD) protein, a member of a family that includes coagulation factors II, VII, IX, and X, protein C, protein S, and protein Z. 2 Despite its structural relationship to these critical components of the clotting system and genetic data suggesting that Gas6 participates in vascular disease, a defined role for Gas6 in fibrin clot formation has remained elusive. Here, Robins et al narrow that gap in our knowledge. Gas6 is the ligand for members of the TAM family of receptor tyrosine kinases (RTKs), Tyro, Axl, and Mer. These single transmembrane RTKs contain a cytoplasmic tyrosine kinase domain that is autophosphory-lated when the receptor dimerizes in response to Gas6 binding to its extracellular domain. Axl, the best characterized, has the highest affinity for Gas6 and like Gas6, is expressed by many cells, including vascular smooth muscle cells, endothelial cells, platelets, monocytes, and bone marrow cells. Gas6-TAM binding induces many biologic effects, promoting reversible growth arrest, cell survival, proliferation , migration, and adhesion (reviewed in Laurance et al 3). Most responses are mediated via activation of phosphatidylinositol-3-kinase (PI3-kinase), although other pathways have been implicated, adding to the complexity of evaluating the role(s) of Gas6 in health and disease. Major insights into the pathophysiologic relevance of Gas6, particularly in the vascula-ture, have been gained through studies using genetically engineered mice. In mouse models of arterial injury or atherosclerosis, deficiency of Gas6 or Axl results in vasculoprotection, with reduced intimal media …