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PMID:18188450

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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

Significance

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


See also

References

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