Lyn kinase plays important roles in erythroid expansion, maturation and Epo-receptor signaling by regulating inhibitory signaling pathways that control survival

Erythroid homeostasis is primarily controlled by Epo-receptor signaling, 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 signaling. Pharmacological inhibition of Lyn with PP2 inhibited the survival of terminally differentiated erythroblasts. Less committed erythroid progenitors expanded well, while 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. Signaling studies showed that Lyn was required for both positive GAB2/Akt/FoxO3 survival signals as well as negative feedback of JAK2/STAT5 and Erk1/2 signals via SHP-1. During differentiation, Lyn controls survival and cell cycle exit as evidenced by reduced STAT5 and FoxO3/GSKa/b 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 red blood cell production by influencing ...

Source: BJ Cell - February 20, 2014 Category: Biochemistry Authors: N S. Slavova-Azmanova, N Kucera, A Louw, J Satiaputra, A Handoko, P Singer, L Stone, D J. McCarthy, S Peter Klinken, M L. Hibbs, E Ingley Tags: BJ Signal Source Type: research