Biomedical Engineering Reference
In-Depth Information
5. BIOCHEMISTRY AND CELL BIOLOGY OF PCP
SIGNALING
PCP components have mostly been identified by genetic analyses.
Much less is understood in terms of biochemical and cell biological mech-
anisms. In addition, neither the upstream regulators of PCP nor the down-
stream effectors that put out the asymmetry in most cases are well
understood. Consistent with that, there has not been reliable or relevant
biochemical readout specific for PCP signaling. JNK and Rac1 activations
are often used in many studies, and they are definitely involved in PCP sig-
naling. However, their exact roles in PCP signaling are unknown because
JNK and Rac1 also respond to many other signaling pathways. Asymmetric
localization of PCP components has been shown to be essential to PCP
signaling. However, how such asymmetric localization is established and
what this asymmetric localization encodes are not clear. The ubiquitin
proteosome system is a key mechanism of asymmetric localization of some
PCP components, suggesting that selective degradation could be a way to
introduce asymmetry (
Narimatsu et al., 2009
). Recent studies established
that endocytosis is required for PCP signaling (
Sato, Yamamoto, Sakane,
Koyama, & Kikuchi, 2010; Yu et al., 2007
). Based on all these findings,
it is possible that multiple signaling events may take place in different
parts of the cell during PCP signaling at the same time or in sequence.
Therefore, it is necessary to understand all the biochemical interactions
among PCP components before
the
complete picture of PCP
mechanisms can emerge.
A recent study on the biochemical interactions of the core PCP compo-
nents led to a possibly general mechanism for setting up and/or maintaining
the asymmetric localization of PCP components (
Shafer et al., 2011
)
(
Fig. 6.3
). The distribution of Frizzled3 protein appears to depend on its state
of phosphorylation. Frizzled3 protein is mostly localized in intracellular
vesicles, and hyperphosphorylation of Frizzled3, induced by Disheveled1,
causes Frizzled3 to be targeted to the plasma membrane (
Fig. 6.3B
). Vangl2,
which antagonizes Disheveled1, reduces Frizzled3 phosphorylation and
membrane localization on the cell surface (
Shafer et al., 2011
)
(
Fig. 6.3C
). These findings are consistent with the observations that Van
Gogh and Prickle tend to have opposite functions from Frizzled and Dishev-
eled in PCP signaling and suggest that the antagonism may be achieved by
opposite effects on Frizzled phosphorylation/membrane localization
