Down regulation of receptor signaling often involves internalization
of the receptor followed by its degradation. Fewer active receptors found on the cell
surface mean lesser capacity for signal. Reduced number of receptors on the
surface also affects the duration of a particular signal. Accordingly, internalization
of FGFR3 will reduce its signaling capacity on the surface and provide an important
regulatory mechanism for decreasing FGFR3 signaling. Internalization of
receptor (by a process called endocytosis) can take place through one or more pathways
as shown in the figure below.
We have previously shown that FGFR3 can be internalized in a
clathrin/dynamin-dependent manner and this is required for receptor cleavage to
occur that generates the soluble intracellular piece (sICD) (Degnin et al, 2011). Others have reported that
FGFR3 may be internalized by both clathrin-dependent and clathrin-independent
mechanisms. The mechanism of FGFR3 degradation has not been clearly delineated.
We have evidence that FGFR3 forms a complex with proteins, called chaperones
that help keep FGFR3 stable. Upon dissociation from the chaperone complex, FGFR3
gets processed and is degraded. The chaperone complexes seem to be important in
maintaining stable FGFR3 and therefore also become important targets that
affect FGFR3 degradation.
