title: Lyn kinase plays important roles in erythroid expansion, maturation and erythropoietin receptor signalling by regulating inhibitory signalling pathways that control survival.
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/GSKα/β (glycogen synthase kinase α/β) phosphorylation and diminished p27(Kip1) 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.
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: Neli S
authors.initials: NS
authors.lastname: Slavova-Azmanova
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kucera
authors.forename: Alison
authors.initials: A
authors.lastname: Louw
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: Jiulia
authors.initials: J
authors.lastname: Satiaputra
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: Adley
authors.initials: A
authors.lastname: Handoko
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Singer
authors.forename: Leah
authors.initials: L
authors.lastname: Stone
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: McCarthy
authors.affiliation: ‡Leukaemia and Blood Disorders Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Klinken
authors.affiliation: §Leukocyte Signalling Laboratory, Department of Immunology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, VIC 3004, Australia.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.affiliation: *Cell Signalling Group, Laboratory for Cancer Medicine, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6008, Australia.
authors.forename: Evan
authors.initials: E
authors.lastname: Ingley
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D006397:Hematinics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C412373:AG 1879; D051017:Apoptosis Regulatory Proteins; C554270:EPO protein, human; D006397:Hematinics; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases