ABSTRACT
Many patients with anemia fail to respond to treatment with erythropoietin (Epo), a commonly used hormone that stimulates erythroid progenitor production and maturation by human BM or by murine spleen. The protein product of growth arrest-specific gene 6 (Gas6) is important for cell survival across several cell types, but its precise physiological role remains largely enigmatic. Here, we report that murine erythroblasts released Gas6 in response to Epo and that Gas6 enhanced Epo receptor signaling by activating the serine-threonine kinase Akt in these cells. In the absence of Gas6, erythroid progenitors and erythroblasts were hyporesponsive to the survival activity of Epo and failed to restore hematocrit levels in response to anemia. In addition, Gas6 may influence erythropoiesis via paracrine erythroblast-independent mechanisms involving macrophages. When mice with acute anemia were treated with Gas6, the protein normalized hematocrit levels without causing undesired erythrocytosis. In a transgenic mouse model of chronic anemia caused by insufficient Epo production, Gas6 synergized with Epo in restoring hematocrit levels. These findings may have implications for the treatment of patients with anemia who fail to adequately respond to Epo.
Subject(s)
Anemia/drug therapy , Anemia/genetics , Erythropoiesis/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/therapeutic use , Animals , Cell Adhesion/genetics , Cell Survival , Disease Models, Animal , Drug Resistance , Erythroblasts/drug effects , Erythroblasts/metabolism , Erythropoietin/genetics , Erythropoietin/pharmacology , Erythropoietin/therapeutic use , Humans , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Mutant Strains , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Erythropoietin/agonists , Recombinant Proteins/genetics , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , c-Mer Tyrosine Kinase , Axl Receptor Tyrosine KinaseABSTRACT
Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing "outside-in" signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. Blocking the Gas6-R-alphaIIbbeta3 integrin cross-talk might be a novel approach to the reduction of thrombosis.
