Biology Reference
In-Depth Information
C
C
C
EPOR
ligand
Extracellular
Domain
R129
WSxWS
Transcellular
Domain
P
Box 1
W282
JAK2
Box 2
Induction of
other pathways
P
Y343
STAT5
Intracellular
Domain
Negative
regulatory
loops
PI-3K
P
Y
P
Y401
Y429
Y431
Y443
Y460
Y464
Y479
STAT5
SHP-2
Y P
CIS
Negative
regulatory
domain
Y
P
SHP-1
Y
P
CrkL
Y P
GrB 2
Y
P
Induction by
other pathways
PI-3K
P
Y
Lyn-K
Y P
Figure 1. Model of the EPO receptor. Important residues or motifs are marked on the left side of the
figure with their abbreviation (Cysteine: C; Tyrosine: Y; Arginine: R; Serine: S; Tryptophan: W) and
position. Important signaling pathways and negative regulatory loops are indicated on the right side
of the model. P indicates the phosphorylation necessary for the activation of the pathway. (Modified
from [25a] and [86].)
tiple forms of EPOR have been identified in EPOR-bearing cells (64 to 78 Kd),
which differ by the degree of glycosylation. Compelling evidence is given that
preferentially EPOR forms with the highest MW bind EPO protein and induce
signal transduction [35]. The extracellular domain of EPOR consists of two
fibronectin type III-like domains (designated
N
- and
N C
-terminal domain), each
of them comprising seven beta strands that are connected by six loops. Most
residues of the extracellular domain involved in the binding of EPO protein are
located on the loops. Phe95 and Phe205 are most important for the binding of
EPO, although other residues are critical for alternative agents activating
EPOR (e.g., Met150 for EPO mimetic peptites) [36, 37]. Arg129, Glu132, and
Glu133 are involved in the dimerization of EPOR. The WSXWS motif is
important for ligand binding and internalization as well as signal transduction
[38, 39].
The intracellular domain is divided in two functional regions. The mem-
brane proximal region is encoded by exon 7 and contains the box 1 and box 2
