Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways

W Tong, J Zhang, HF Lodish - Blood, 2005 - ashpublications.org
W Tong, J Zhang, HF Lodish
Blood, 2005ashpublications.org
Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell
development. Upon Epo addition, the EpoR signaling through the Janus kinase 2 (JAK2)
activates multiple pathways including Stat5, phosphoinositide-3 kinase (PI-3K)/Akt, and
p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in
cytokine receptor signaling. Here, we showed that Lnk-deficient mice have elevated
numbers of erythroid progenitors, and that splenic erythroid colony-forming unit (CFU-e) …
Abstract
Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell development. Upon Epo addition, the EpoR signaling through the Janus kinase 2 (JAK2) activates multiple pathways including Stat5, phosphoinositide-3 kinase (PI-3K)/Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor signaling. Here, we showed that Lnk-deficient mice have elevated numbers of erythroid progenitors, and that splenic erythroid colony-forming unit (CFU-e) progenitors are hypersensitive to Epo. Lnk-/- mice also exhibit superior recovery after erythropoietic stress. In addition, Lnk deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors. Conversely, Lnk overexpression inhibits Epo-induced cell growth in 32D/EpoR cells. In primary culture of fetal liver cells, Lnk overexpression inhibits Epo-dependent erythroblast differentiation and induces apoptosis. Lnk blocks 3 major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. In addition, the Lnk Src homology 2 (SH2) domain is essential for its inhibitory function, whereas the conserved tyrosine near the C-terminus and the pleckstrin homology (PH) domain of Lnk are not critical. Furthermore, wild-type Lnk, but not the Lnk SH2 mutant, becomes tyrosine-phosphorylated following Epo administration and inhibits EpoR phosphorylation and JAK2 activation. Hence, Lnk, through its SH2 domain, negatively modulates EpoR signaling by attenuating JAK2 activation, and regulates Epo-mediated erythropoiesis. (Blood. 2005; 105:4604-4612)
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