Question

47. The binding of erythropoietin to the

erythropoietin receptor (EpoR) stimulates
intracellular signaling in certain cells, which
causes them to differentiate to red blood cells.
The EpoR is a transmembrane protein with two
cytoplasmic domains, each of which is bound by
a kinase protein, JAK2. The binding of
erythropoietin to the EpoR causes the
cytoplasmic domains of the EpoR to undergo
conformational changes that activate the bound
JAK2 kinases. The JAK2 kinases then
phosphorylate several intracellular proteins,
including STATS, whose resulting activity
causes the cells to differentiate to red blood
cells.
Which of the following explains how a mutation
that removes a portion of each cytoplasmic
domain of EpoR most likely affects
differentiation of the cells?
(A) The cells will differentiate more rapidly
than they typically do because the JAK2
kinases will always be active.
(B) The cells will mature to another cell type
because the JAK2 kinases will
phosphorylate inappropriate cellular
proteins.
(C) STATS will not be activated because
erythropoietin cannot bind to the EpoR.
(D) STATS will not be activated because it will
not be phosphorylated by the JAK2
kinases.

Answer 1

Erythropoietin (Epo) is required for the production of mature red blood cells. The requirement for Epo and its receptor (EpoR) for normal heart development and the response of vascular endothelium and cells of neural origin to Epo provide evidence that the function of Epo as a growth factor or cytokine to protect cells from apoptosis extends beyond the hematopoietic lineage. We now report that the EpoR is expressed on myoblasts and can mediate a biological response of these cells to treatment with Epo. Primary murine satellite cells and myoblast C2C12 cells, both of which express endogenous EpoR, exhibit a proliferative response to Epo and a marked decrease in terminal differentiation to form myotubes. We also observed that Epo stimulation activates Jak2/Stat5 signal transduction and increases cytoplasmic calcium, which is dependent on tyrosine phosphorylation. In erythroid progenitor cells, Epo stimulates induction of transcription factor GATA-1 and EpoR; in C2C12 cells, GATA-3 and EpoR expression are induced. The decrease in differentiation of C2C12 cells is concomitant with an increase in Myf-5 and MyoD expression and inhibition of myogenin induction during differentiation, altering the pattern of expression of the MyoD family of transcription factors during muscle differentiation. These data suggest that, rather than acting in an instructive or specific mode for differentiation, Epo can stimulate proliferation of myoblasts to expand the progenitor population during differentiation and may have a potential role in muscle development or repair.