title: Role of Gas6 in erythropoiesis and anemia in mice.
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.
authors.affiliation: Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois, University Hospital Center, University of Lausanne, Lausanne, Switzerland. Anne.Angellilo-Scherrer@chuv.ch
authors.forename: Anne
authors.initials: A
authors.lastname: Angelillo-Scherrer
authors.forename: Laurent
authors.initials: L
authors.lastname: Burnier
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fish
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Stéphane
authors.initials: S
authors.lastname: Plaisance
authors.forename: Rocco
authors.initials: R
authors.lastname: Sugamele
authors.forename: Maria
authors.initials: M
authors.lastname: DeMol
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martinez-Soria
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Goff
authors.forename: Glenn K
authors.initials: GK
authors.lastname: Matsushima
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
authors.forename: Marc
authors.initials: M
authors.lastname: Schapira
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000235:genetics*; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002470:Cell Survival; D004195:Disease Models, Animal; D004351:Drug Resistance; D004900:Erythroblasts / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D004921:Erythropoietin / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D051379:Mice; D008817:Mice, Mutant Strains; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000819:agonists; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D004921:Erythropoietin; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C490767:Mertk protein, mouse; C513478:Tyro3 protein, mouse