The Role of Arrestins in Development - Progress in Molecular Biology and Translational Science - page 227

A rrestin

Smoothened-mediated
Hedgehog signaling
(mouse, zebrafish)

GliA

A rrestin

Smo

S hh

Gas8

Ptch1

GRK2

CK1

Figure 9.3 b-Arrestin 2 and vertebrate Hedgehog signaling. Vertebrate Hedgehog sig-
naling depends greatly on the translocation of required signaling molecules to primary
cilia. Importantly, barr2 physically links Smoothened to a kinesin motor and thus facil-
itates the ciliary shuttling of Smoothened.

4.3.1 b arr2 in Hh signaling
Similar to classic GPCRs, phosphorylation of active Smo by GRK2 and
recruitment of arr2 to the plasma membrane results in Smo internalization

through clathrin-mediated endocytosis in nonciliated HEK293 cells. 73
Interestingly, both GRK2 and

b

b arr2 actively promote Hh signaling, as

b

GRK2 and arr2 knockdown in zebrafish embryos recapitulates Hh loss-

of-function phenotypes. 17,18,27 Similar to the typical phenotypes of smu
mutant fish, b arr2 and GRK2 morphants display a ventrally curved body
and misshaped somites at 24 hours post fertilization (hpf). 18,27 arr2 and

GRK2 morphants also show impaired muscle development, manifest by
reduced numbers of muscle pioneer cells and slow muscle fibers, 17,18,27
whose formation requires Shh secretion from the notochord. 74 These phe-
notypes are accompanied by reduced expression of Hh downstream target

b