Integrating novel signaling pathways involved in erythropoiesis

Abstract

Many extrinsic and intrinsic factors control the development of red blood cells from committed progenitors, with the Erythropoietin‐receptor (Epo‐R) signaling network being the primary controlling molecular hub. Although much is understood about erythroid signaling pathways, new and intriguing factors that influence different aspects of erythroid cell development are still being uncovered. New extrinsic effectors include hypoxia and polymeric IgA1 (pIgA1), and new Epo‐R signaling pathway components include Lyn/Cbp and Lyn/Liar. Hypoxia directly activates committed erythroid progenitors to expand, whereas pIgA1 activates the Akt and MAP‐Kinase (MAPK) pathways through transferrin receptors on more mature erythroid cells. The Lyn/Cbp pathway controls the activity and protein levels of Lyn through recruitment of Csk and SOCS1, as well as feeding into the control of other pathways mediated by recruitment of ras‐GAP, PI3‐kinase, PLCγ, Fes, and EBP50. Nuclear/cytoplasmic shuttling of Lyn and other signaling molecules is influenced by Liar and results in regulation of their intersecting signaling pathways. The challenge of future research is to flesh out the details of these new signaling regulators/networks and integrate their influences during the different stages of erythropoiesis. 2012 IUBMB IUBMB Life, 2012

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis

“…As shown in Figure 4F, downstream of STAT5 and suggests that Fyn is implicated in EPO signaling pathway by modulating the activation of EPO-R through STAT5. Similar findings have been reported for mice genetically lacking Lyn, 50 supporting the important and nonredundant role of Fyn in the EPO-mediated signaling cascade. Our findings also suggest that multiple kinases may be important in coordinating stress erythropoiesis in health and disease.…”

“…Collectively, these data support the idea that by activating autophagy it is possible to rescue the altered response of Fyn −/− mice to stress erythropoiesis.4 | DISCUSSIONWe have identified Fyn as a new kinase involved in EPO signaling cascade during normal and stress erythropoiesis. Previous studies have documented a similar role for Jak2 and Lyn kinases in erythropoiesis [2][3][4]50,51. The reduction in EPO induced phosphorylation of STAT5 noted in Fyn −/− mouse erythroid cells implies a role for Fyn…”

Direct targets of pSTAT5 signalling in erythropoiesis

“…Gain-of-function mutations in p85 lead to constitutive EpoR activity whereas p85 knockout mice display anemia [16]. The raf-MAPK and LYN kinase pathways are also activated in erythroid cells by EPO [17]. A truncated EpoR containing the binding site for pSTAT5 (Y343), but missing C-terminal Y residues, is sufficient to rescue responses to anemic stress in vivo [9], suggesting STAT5 engagement is critical.…”

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

“…Moreover, STAT5 phosphorylation is Epo dependent, but independent of constitutive JAK2 phosphorylation. Epo-R signaling can also stimulate STAT1 and STAT3 phosphorylation, 27 and we show that J2-Lyn 1/up cells have enhanced Epo-induced STAT3 phosphorylation, whereas STAT1 phosphorylation is reduced ( Figure 6B). The regulation of downstream pathways from the Epo-R is controlled by recruitment and phosphorylation of not only the receptor itself but also several adaptors/scaffolds and phosphatases.…”