PMID:18188450

Citation	Angelillo-Scherrer, A, Burnier, L, Lambrechts, D, Fish, RJ, Tjwa, M, Plaisance, S, Sugamele, R, DeMol, M, Martinez-Soria, E, Maxwell, PH, Lemke, G, Goff, SP, Matsushima, GK, Earp, HS, Chanson, M, Collen, D, Izui, S, Schapira, M, Conway, EM and Carmeliet, P (2008) Role of Gas6 in erythropoiesis and anemia in mice. J. Clin. Invest. 118:583-96
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.
Links	PubMed PMC2176185 Online version:10.1172/JCI30375
Keywords	Anemia/drug therapy; Anemia/genetics; Animals; Cell Adhesion/genetics; Cell Survival; Disease Models, Animal; Drug Resistance; Erythroblasts/drug effects; Erythroblasts/metabolism; Erythropoiesis/genetics; Erythropoietin/genetics; Erythropoietin/pharmacology; Erythropoietin/therapeutic use; Humans; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism; Intercellular Signaling Peptides and Proteins/therapeutic use; 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
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:UFO	acts_upstream_of_or_within	GO:0034101: erythrocyte homeostasis	ECO:0000316: genetic interaction evidence used in manual assertion	MGI:MGI:95660	P		Seeded From UniProt	complete
MOUSE:UFO	acts_upstream_of_or_within	GO:0034101: erythrocyte homeostasis	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:2387750	P		Seeded From UniProt	complete
MOUSE:GAS6	part_of	GO:0005615: extracellular space	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(CL:0000765)	Seeded From UniProt	complete
MOUSE:GAS6	acts_upstream_of_or_within	GO:0043066: negative regulation of apoptotic process	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:2675495	P	regulates_o_occurs_in:(CL:0000765)	Seeded From UniProt	complete
MOUSE:GAS6	acts_upstream_of_or_within	GO:0043491: protein kinase B signaling	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:2675495	P	occurs_in:(CL:0000765)	Seeded From UniProt	complete
MOUSE:GAS6	acts_upstream_of_or_within	GO:0031589: cell-substrate adhesion	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:2675495	P		Seeded From UniProt	complete
MOUSE:GAS6	acts_upstream_of_or_within	GO:0071363: cellular response to growth factor stimulus	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:2675495	P	occurs_in:(CL:0000765)	Seeded From UniProt	complete

References

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