Biomedical Engineering Reference
In-Depth Information
ligand-bound receptors in the endosomal compartments can still trigger
downstream responses even when morphogen is no longer present in the
extracellular matrix (
Jullien & Gurdon, 2005
). In the canonical Wnt signal-
ing pathway, while early genetic analysis in
Drosophila
indicated that
endocytic trafficking degrades Wingless protein, supporting a traditional
view of signaling termination through receptor downregulation (
Dubois,
Lecourtois, Alexandre, Hirst, & Vincent, 2001
), later studies show that
endocytosis plays a positive role and suggest that maximal signal activities
are generated from endosomes (
Blitzer & Nusse, 2006; Seto & Bellen,
2006
). Either knocking down Dynamin or Rab5 (a small GTPase
required for early stages of endocytosis) in
Drosophila
S2R
รพ
cells or
overexpressing dominant-negative forms of them in
Drosophila
wing
imaginal discs reduced Wingless signaling (
Seto & Bellen, 2006
). In a
mammalian cell culture system, blocking endocytosis by interfering
Dynamin function or drug treatment also decreased the levels of
b
-catenin and Wnt target gene expression when more exogenous Wnt
proteins accumulated on the membrane (
Blitzer & Nusse, 2006
). Studies
on
b
-arrestin, which links receptor proteins to clathrin and clathrin
adaptor AP-2 to promote endocytosis, supported the positive role of
clathrin-mediated endocytosis in Wnt/
b
-catenin signaling (
Bryja, Gradl,
Schambony, Arenas, & Schulte, 2007
). In addition, another major
endocytic route, caveolin-mediated endocytosis, was found to be
necessary for canonical Wnt signal transduction as well (
Yamamoto,
Komekado, & Kikuchi, 2006
). In the Wnt/PCP pathway, important role
of intracellular trafficking has also been implicated. Sec24b, a member of
COPII coat protein complex that transports proteins from endoplasmic
reticulum to Golgi, was identified to selectively transport core PCP
protein Vangl2.
Sec24b
mutant mice exhibited craniorachischisis and
decreased Vangl2 membrane localization (
Merte et al., 2010; Wansleeben
et al., 2010
). Involvement of endocytosis in PCP was first suggested by
Eaton's group (
Classen, Anderson, Marois, & Eaton, 2005
). During
development,
Drosophila
wing epithelial cells gradually become
hexagonally packed shortly before hair formation in a PCP-dependent
manner. They proposed a model in which PCP proteins polarize
cadherin endocytosis and recycling leading to the cellular packing
geometry in the fly wing (
Classen et al., 2005
). Later on, it is found that
interactions between Disheveled and AP-2 appear to be required for PCP
activity through engaging Wnt5a-dependent internalization of Frizzled4
(
Yu et al., 2007
). Along this
line,
it has been shown before that
