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Erythropoietin induces association of the JAK2 protein tyrosine kinase with
the erythropoietin receptor in vivo
O Miura, N Nakamura, FW Quelle, BA Witthuhn, JN Ihle and N Aoki
First Department of Internal Medicine, Tokyo Medical and Dental University,
Japan.
Protein tyrosine phosphorylation has been hypothesized to play a key role
in the growth signaling induced by erythropoietin (Epo), although the Epo
receptor (EpoR), a member of the cytokine receptor superfamily, lacks a
tyrosine kinase domain. Recently, the JAK2 tyrosine kinase was shown to be
activated on Epo stimulation and to bind to the cytoplasmic domain of EpoR
in vitro. To further explore the mechanisms of activation of JAK2 in
EpoR-mediated signal transduction, we assessed the conditions for
association of JAK2 with EpoR in vivo. Epo stimulation rapidly induced
association of JAK2 with the EpoR in an interleukin 3 (IL-3)-dependent cell
line transfected with the wild-type EpoR. On Epo stimulation JAK2 also
associated with a truncated mutant EpoR (H-mutant), which is
mitogenetically active but not tyrosine phosphorylated, indicating that
association does not require receptor phosphorylation and occurs in the
membrane proximal region. However, association was not detected with mutant
receptors inactivated by an internal deletion or a point mutation, Trp282
to Arg, in a membrane- proximal cytoplasmic region (PB or PM4 mutant,
respectively). Immune complex kinase assays of anti-EpoR immunoprecipitates
also revealed that activated JAK2 associates with the EpoR in
Epo-stimulated cells. By this approach, association also occurred with the
mitogenically active H mutant but not with the mitogenically inactive PB or
PM4 mutants. In the immune complex kinases assays, EpoR, JAK2, and a 150-kD
protein were phosphorylated on tyrosine. Taken together, the results
further support the hypothesis that, on Epo stimulation, JAK2 associates
with the membrane-proximal cytoplasmic region of the EpoR to be activated
and induces tyrosine phosphorylation of cellular substrates, including the
EpoR, to transduce a growth signal.
Volume 84,
Issue 5,
pp. 1501-1507,
09/01/1994
Copyright © 1994 by The American Society of Hematology
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