The Role of Arrestins in Development - Progress in Molecular Biology and Translational Science - page 221

knockdown embryos are therefore indistinguishable from controls up to
gastrulation. Knockdown may be observed only at the point where embry-
onic protein synthesis outpaces maternally supplied protein content.
To date, no loss-of-function mutant for either b arr in aquatic models has

been reported.

3. THE FUNCTION OF ARRESTINS IN INVERTEBRATES
A growing number of studies in Drosophila suggest that the fly ortholog
of vertebrate arr is only partially functionally conserved from invertebrates

to vertebrates. kurtz , the only nonvisual

b

arr in Drosophila , is ubiquitously
expressed during early embryogenesis. At later stages, it becomes more local-
ized to the larval central nervous system and fat bodies, a tissue fulfilling a
similar function as the vertebrate liver. Similar to b arr2b knockdown in
zebrafish 18 and the

b

arr1/2 double KO in mice, 9 loss of kurtz is incompatible
with normal embryonic development. 13 Fly embryos deficient in kurtz are
immobile and do not survive the larval-pupal transition. Prior to their death,
the kurtz mutants display melanotic tumors, which are formed on the surface
of their abnormal fat bodies. Interestingly, reconstitution of kurtz exclusively
in the central nervous system rescues the mutant lethality and phenotypes,
although not fully. 13 Furthermore, maternal loss of kurtz was found to
interfere with receptor tyrosine kinase signaling toward MAP kinases as well
as Toll/NF k B signaling. 20 By binding to inactive ERK, kurtz sequesters
ERK and prevents its activation. This is in contrast to vertebrates, where the
b

b

arr-mediated assembly of signaling complexes propagates ERK activation
and signaling. 21
On the other hand, very akin to mammalian arr1 and 2, 22 kurtz limits

b

B. 20 NF k B signaling by association with cactus, the Drosophila homolog of I k

Another striking difference with the vertebrate actions of arr on signal

transduction can be found in Smo-mediated Hedgehog (Hh) signal trans-
duction. kurtz appears to limit Hh signaling, rather than promoting it as seen
in different vertebrate systems. 17,18,23 Loss of kurtz has no effect on Hh sig-
naling, whereas ectopic expression of kurtz phenocopies Hh loss of func-
tion. 24 Flies overexpressing kurtz develop smaller wings and display
downregulation of patched , the negative feedback loop target of the Hh
pathway. This is because kurtz promotes the internalization of Smo by bind-
ing to its C tail, 25 subsequently leading to its proteasomal degradation. 24
Interestingly, this action is independent of GPCR kinases (GRKs), which
were shown to facilitate Hh signaling in vertebrates. 26,27 In fact, combining

b