Biology Reference
In-Depth Information
Figure 1. Binding of EPO induces a conformational change in the receptor dimer that is transmitted
to the cytosolic domain, leading to auto- or transphosphorylation of JAK-2. JAK-2 kinase then phos-
phorylates several tyrosine residues in EPOR, creating docking sites for the SH2 domains of several
signal transduction proteins. These signaling proteins become activated and downstream signal trans-
duction is initiated. One of the mechanisms of terminating EPOR signal transduction is through the
protein tyrosine phosphatase SHP1. SHP1 binding to a segment of EPOR containing phosphotyrosine
429 induces activation of the phosphatase. SHP1 then removes the activating phosphate from JAK-2,
and terminates signal transduction.
Preformed unliganded EPOR oligomers on the surface of living cells are not
active, and a fusion protein of EPOR with its transmembrane domain replaced
with the transmembrane domain of glycophorin A, shown to mediate dimer
formation, also requires EPO for activation [25]. The latter paper concludes
that interactions between the transmembrane domains of unliganded EPOR
maintains them in an inactive state. These and other results [20] suggest that
inactive EPOR are converted to an active state upon EPO binding through a
rotational movement instead of a lateral movement of the two transmembrane
domains to achieve functional proximity of the cytoplasmic domains (Fig.2).
This model contradicts one based on crystallographic structures of liganded
and unliganded EPOR that proposes a decrease in the distance between the two
transmembrane domains upon ligand binding to preformed EPOR dimers [21,
23]. Thus, the mechanism by which EPO binding leads to receptor activation
remains unknown.
