Lyn deficiency reduces GATA-1, EKLF and STAT5, and induces extramedullary stress erythropoiesis

Abstract

In vitro studies have implicated the Lyn tyrosine kinase in erythropoietin signaling. In this study, we show that J2E erythroid cells lacking Lyn have impaired signaling and reduced levels of transcription factors STAT5a, EKLF and GATA-1. Since mice lacking STAT5, EKLF or GATA-1 have red cell abnormalities, this study also examined the erythroid compartment of Lyn À/À mice. Significantly, STAT5, EKLF and GATA-1 levels were appreciably lower in Lyn À/À erythroblasts, and the phenotype of Lyn À/À animals was remarkably similar to GATA-1 low animals. Although young adult Lyn-deficient mice had normal hematocrits, older mice developed anemia. Grossly enlarged erythroblasts and florid erythrophagocytosis were detected in the bone marrow of mice lacking Lyn. Markedly elevated erythroid progenitors and precursor levels were observed in the spleens, but not bone marrow, of Lyn À/À animals indicating that extramedullary erythropoiesis was occurring. These data indicate that Lyn À/À mice display extramedullary stress erythropoiesis to compensate for intrinsic and extrinsic erythroid defects.

Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells

“…Importantly, the absence of Lyn, or prolonged activation of Lyn, have deleterious consequences for the hemopoietic compartment in vivo (26,27,55). The data presented here add to the understanding of the intricate mechanisms involved in the control of Src family kinases.…”

“…Cells were stimulated with Epo (5 units/ml) in media containing T 3 depleted FCS (36), and hemoglobin production detected by benzidine staining (21). Splenic erythroblasts were isolated from phenylhydrazinetreated Lyn ϩ/ϩ and Lyn Ϫ/Ϫ mice as described previously (26).…”

“…Lyn remains an active kinase in erythrocytes, and is capable of phosphorylating the structural protein Band 3 (25). The effects of Lyn on erythroid cells are not restricted to in vitro systems, as Lyn Ϫ/Ϫ mice display extramedullary stress erythropoiesis and eventually become anemic (26,27).…”

Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling

“…[1][2][3][4] JAK2 is recognized as the kinase involved in initiation of Epo receptor signaling, 1 whereas Lyn, a member of the Src family of tyrosine kinases (SFKs), has been implicated as a key secondary kinase. [5][6][7][8][9][10] In vitro studies established a role for Lyn in Epo receptor signaling 6,11 and demonstrated that Epo signaling in immortalized J2E-derived cells appeared identical to primary erythroid cells. 6,9,11 Subsequent studies using Lyn 2/2 mice consolidated the importance of this SFK for early erythroid cell expansion and late-stage maturation.…”

“…[5][6][7][8][9][10] In vitro studies established a role for Lyn in Epo receptor signaling 6,11 and demonstrated that Epo signaling in immortalized J2E-derived cells appeared identical to primary erythroid cells. 6,9,11 Subsequent studies using Lyn 2/2 mice consolidated the importance of this SFK for early erythroid cell expansion and late-stage maturation. [8][9][10] Removal, or inhibition, of Lyn attenuates the ability of erythroid cells to differentiate in response to Epo.…”