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b
drives CGNPs cell cycle exit. Accordingly, blocking
arr1 with shRNA
leads to the opposite effect and increased cell proliferation.
84
Thus, in addi-
tion to the well-known negative feedback of Shh signaling through
increased transcription of the Smo inhibitor Ptch1, Shh also induces
arr1
translocation to the nucleus, where it facilitates transcription of a CDK
inhibitor, thereby negatively regulating mitogenic Shh signaling.
b
5. CONCLUSIONS
b
arrs were first identified more than 20 years ago, they were
believed to simply put a halt on G protein-coupled receptor signaling. Since
then
b
arrs have been studied extensively. Approaches with purified proteins,
heterologous cell systems, and finally genetically engineered mice illustrated
that
When
arrs are in fact multifunctional integrators of many different signaling
cascades. Apart from their function in the regulation of canonical GPCR
signaling,
b
arrs modulate the signaling function of atypical 7TM proteins
such as Smo and Frizzled proteins. This function has gained intense interest
in the arrestin community. Experiments using frogs, flies, and zebrafish have
further emphasized the importance of
b
arrs in the Hh and Wnt pathways.
Even more, these reports have emphasized that arrestins are important sig-
naling molecules during embryonic development. So far, we know that
b
b
arrs steer hematopoiesis and regulate cell cycle progression, in part because
they are regulated themselves. In addition,
arrs drive lung morphogenesis
and muscle and cartilage development. Not all findings obtained in lower
model organisms can be related to mammals. But nevertheless, it has become
apparent that
b
arrs have multiple functions in cellular signaling and thus
govern many physiological as well as pathological processes in the embryo.
b
ACKNOWLEDGMENTS
Work from the authors' laboratories reviewed in this chapter was supported in part by grants
from the National Institutes of Health: NS-019576 and MH-073853 (M. G. C.). T. E. was
supported by a fellowship from the Machiah Foundation. Melanie Philipp is the recipient of
a Marie Curie Reintegration Grant (268333) and a grant by the Deutsche Stiftung f¨ r
Herzforschung (F/09/11).
REFERENCES
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