1. Role of Gas6 in erythropoiesis and anemia in mice
- Author
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Eduardo Martinez-Soria, Shozo Izui, Marc Chanson, Laurent Burnier, Peter Carmeliet, Stephen P. Goff, Greg Lemke, Marc Tjwa, Anne Angelillo-Scherrer, Desire Collen, Marc Schapira, Maria DeMol, Patrick H. Maxwell, Glenn K. Matsushima, Richard J. Fish, H. Shelton Earp, Rocco Sugamele, Diether Lambrechts, Edward M. Conway, and Stéphane Plaisance
- Subjects
Erythroblasts ,Oncogene Proteins/genetics/metabolism ,Anemia/drug therapy/genetics ,Drug Resistance ,ddc:616.07 ,Mice ,hemic and lymphatic diseases ,Proto-Oncogene Proteins c-akt/metabolism ,Receptors, Erythropoietin ,Erythropoiesis ,Receptors, Erythropoietin/agonists ,Oncogene Proteins ,ddc:618 ,Anemia ,General Medicine ,Recombinant Proteins ,medicine.anatomical_structure ,Medicine ,Intercellular Signaling Peptides and Proteins ,medicine.drug ,Research Article ,Cell Adhesion/genetics ,Erythropoietin/genetics/pharmacology/therapeutic use ,Cell Survival ,Erythroblasts/drug effects/metabolism ,C-Mer Tyrosine Kinase ,Biology ,Paracrine signalling ,Proto-Oncogene Proteins ,medicine ,Cell Adhesion ,Intercellular Signaling Peptides and Proteins/genetics/metabolism/therapeutic use ,Animals ,Humans ,Progenitor cell ,Protein kinase B ,Erythropoietin ,c-Mer Tyrosine Kinase ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Proto-Oncogene Proteins/metabolism ,Erythropoiesis/genetics ,Axl Receptor Tyrosine Kinase ,Mice, Mutant Strains ,Disease Models, Animal ,Cancer research ,Recombinant Proteins/genetics/pharmacology/therapeutic use ,Bone marrow ,Receptor Protein-Tyrosine Kinases/genetics/metabolism ,Cytology ,Proto-Oncogene Proteins c-akt - 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.
- Published
- 2006