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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia / drug therapy*
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Anemia / genetics*
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Animals
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Axl Receptor Tyrosine Kinase
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Cell Adhesion / genetics
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Cell Survival
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Disease Models, Animal
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Drug Resistance
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Erythroblasts / drug effects
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Erythroblasts / metabolism
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Erythropoiesis / genetics*
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Erythropoietin / genetics
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Erythropoietin / pharmacology
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Erythropoietin / therapeutic use
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / therapeutic use*
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Mice
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Mice, Mutant Strains
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Erythropoietin / agonists
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Recombinant Proteins / therapeutic use
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c-Mer Tyrosine Kinase
Substances
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Intercellular Signaling Peptides and Proteins
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Oncogene Proteins
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Proto-Oncogene Proteins
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Receptors, Erythropoietin
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Recombinant Proteins
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growth arrest-specific protein 6
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Erythropoietin
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Mertk protein, mouse
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Receptor Protein-Tyrosine Kinases
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Tyro3 protein, mouse
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c-Mer Tyrosine Kinase
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Proto-Oncogene Proteins c-akt
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Axl Receptor Tyrosine Kinase