Journal article
Lyn kinase plays important roles in erythroid expansion, maturation and erythropoietin receptor signalling by regulating inhibitory signalling pathways that control survival
Biochemical Journal, Vol.459(3), pp.455-466
2014
Abstract
Erythroid homoeostasis is primarily controlled by Epo (erythropoietin) receptor signalling; however, the Lyn tyrosine kinase plays an important subsidiary role in regulating the erythroid compartment. Nonetheless, specific erythroid pathways that require Lyn activity and their biological significance remain unclear. To address this, we asked what consequence loss of Lyn had on the ex vivo expansion and maturation of splenic erythroid progenitors and Epo receptor signalling. Pharmacological inhibition of Lyn with PP2 inhibited the survival of terminally differentiated erythroblasts. Less committed erythroid progenitors expanded well, whereas early splenic Lyn-/- erythroblasts had attenuated ex vivo expansion, and late stage Lyn-/-erythroblasts were retarded in completing morphological maturation ex vivo. Furthermore, immortalized Lyn-/-erythroblasts were slower growing, less viable and inhibited in their differentiation. Signalling studies showed that Lyn was required for both positive GAB2/Akt/FoxO3 (forkhead box O3) survival signals as well as negative feedback of JAK2 (Janus kinase 2)/STAT5 (signal transducer and activator of transcription 5) and ERK1/2 (extracellular-signal-regulated kinase 1/2) signals via SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase 1). During differentiation, Lyn controls survival and cell cycle exit as demonstrated by reduced STAT5 and FoxO3/GSKa/ß (glycogen synthase kinase a/ß) phosphorylation and diminished p27Kip1 induction in Lyn-deficient erythroblasts. Lyn deficiency alters the balance of pro-and anti-apoptotic molecules (BAD and BclXL), thereby reducing survival and preventing cell cycle exit. Consequently, Lyn facilitates normal erythrocyte production by influencing different stages of erythroid progenitor expansion, and mature cell development and survival signalling.
Details
- Title
- Lyn kinase plays important roles in erythroid expansion, maturation and erythropoietin receptor signalling by regulating inhibitory signalling pathways that control survival
- Authors/Creators
- N.S. Slavova-Azmanova (Author/Creator) - Harry Perkins Institute of Medical ResearchN. Kucera (Author/Creator) - Harry Perkins Institute of Medical ResearchA. Louw (Author/Creator) - Harry Perkins Institute of Medical ResearchJ. Satiaputra (Author/Creator) - Harry Perkins Institute of Medical ResearchA. Handoko (Author/Creator) - Harry Perkins Institute of Medical ResearchP. Singer (Author/Creator) - Harry Perkins Institute of Medical ResearchL. Stone (Author/Creator) - Harry Perkins Institute of Medical ResearchD.J. McCarthy (Author/Creator) - Harry Perkins Institute of Medical ResearchS.P. Klinken (Author/Creator) - Harry Perkins Institute of Medical ResearchM.L. Hibbs (Author/Creator) - Monash UniversityE. Ingley (Author/Creator) - Harry Perkins Institute of Medical Research
- Publication Details
- Biochemical Journal, Vol.459(3), pp.455-466
- Publisher
- Portland Press, Ltd.
- Identifiers
- 991005544309607891
- Copyright
- © 2014 Biochemical Society.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.184 Physiology & Metals
- 1.184.1030 Erythropoietin Therapy
- Web Of Science research areas
- Biochemistry & Molecular Biology
- ESI research areas
- Biology & Biochemistry