Most
mammalian cells express three abundant high affinity receptors,
which can bind and be cross-linked to TGF beta: the type
I (53 kDa), type II (65 kDa), and type III (100-280 kDa)
receptors, based upon the molecular mass of the cross-linked
products analyzed by gel electrophoresis. Tbeta-RI and
Tbeta-RII, the type I and II receptors, are type I transmembrane
proteins with cytosolic domains containing a serine-threonine
kinase. Both receptors are essential for signal transduction.
The TGF-beta type III receptor, or betaglycan, is a membrane-bound
proteoglycan with a short cytoplasmic tail that has no
apparent signaling motif. It binds TGF beta 2 (apparent
Kd 100 pM) with slightly greater affinity than TGF beta
1 or TGF beta 3 (apparent Kda 300 pM). The main role of
beta glycan seems to be in binding and then presenting
TGF beta ligand to the signaling receptors Tbeta-RI and
Tbeta- RII; overexpression of Tbeta-RIII in L6 myoblasts
leads to a dramatic increase in TGF beta 2 binding to Tbeta-RI
and Tbeta-RII.
Following stimulation of cells with a
TGF beta-like protein (e.g. TGF beta 1, TGF beta 3, activins
or dpp), the growth
factor binds to a type II receptor, which in turn recruits
a type I receptor into a heteromeric complex. This is required
for the subsequent phosphorylation of the type I receptor
in the GS-domain by the type II receptor, which leads to
receptor I activation and signal generation. In the case
of ligands with low affinity for the type II receptor (e.g.,
TGF beta 2), accessory receptors such as beta glycan (RIII)
may first recruit the ligand and then present it to the
signalling
complex. The SMAD proteins constitute a unique signaling
pathway with key roles in signal transduction by TGF-beta
and related factors. Pathway restricted SMADs are phosphorylated
and activated by type I receptors in response to stimulation
by ligand. Once activated, pathway - restricted SMADs oligomerize
with the common mediator Smad4 and subsequently translocate
to the nucleus. |
