Reference Report

Reference
Citation	Cheng, S., Maier, D., Hipfner, D.R. (2012). Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling. Development 139(1): 85--94. (Export to RIS)
FlyBase ID	FBrf0216860
Publication Type	Research paper
PubMed ID	22096079
PubMed Abstract	G-protein-coupled receptor kinases (GRKs) play a conserved role in Hedgehog (Hh) signaling. In several systems, GRKs are required for efficient Hh target gene expression. Their principal target appears to be Smoothened (Smo), the intracellular signal-generating component of the pathway and a member of the G-protein-coupled receptor (GPCR) protein family. In Drosophila, a GRK called Gprk2 is needed for internalization and downregulation of activated Smo, consistent with the typical role of these kinases in negatively regulating GPCRs. However, Hh target gene activation is strongly impaired in gprk2 mutant flies, indicating that Gprk2 must also positively regulate Hh signaling at some level. To investigate its function in signaling, we analyzed several different readouts of Hh pathway activity in animals or cells lacking Gprk2. Surprisingly, although target gene expression was impaired, Smo-dependent activation of downstream components of the signaling pathway was increased in the absence of Gprk2. This suggests that Gprk2 does indeed play a role in terminating Smo signaling. However, loss of Gprk2 resulted in a decrease in cellular cAMP concentrations to a level that was limiting for Hh target gene activation. Normal expression of target genes was restored in gprk2 mutants by stimulating cAMP production or activating the cAMP-dependent Protein kinase A (Pka). Our results suggest that direct regulation of Smo by Gprk2 is not absolutely required for Hh target gene expression. Gprk2 is important for normal cAMP regulation, and thus has an indirect effect on the activity of Pka-regulated components of the Hh pathway, including Smo itself.
DOI	10.1242/dev.068817
Related Publication(s)
Recent Updates
Description	What does this section display? This section contains items that were added to this record for each release. It currently only tracks new links between this FlyBase report and other FlyBase data classes (e.g. genes, references, stocks) or controlled vocabulary terms (e.g. GO, anatomy terms). What does this section not display? This section does not currently display links that were removed or gene model changes.
Update Feed	Click the icon below to subscribe to this FlyBase record and receive updates automatically through your feed reader.
FB2013_03
FB2013_02
All updates	Click here to see a list of all updates to this record from FB2010_08 and on.
Associated Information
Comments
Associated Files
Other Information
Secondary IDs
Language of Publication	English
Additional Languages of Abstract
Also Published As
Parent Publication
Publication Type	Journal
Abbreviation	Development
Title	Development
Publication Year	1987-
ISBN/ISSN	0950-1991
Data from Reference
Aberrations (2)
	Df(3R)Gprk2 Df(3R)Gprk2-del1
Alleles (16)
	fu¹ fu⁵⁴ Gprk2^KO Gprk2^Scer\UAS.cCa Gαi^{Q205L.Scer\UAS} Gαs^{Q215L.Scer\UAS} Mmus\Pkaca^mC.Scer\UAS Pka-C1^DN Pka-C1^H2 Pka-R1^BGD.Scer\UAS ptc^Scer\UAS.cJa Scer\GAL4^ap-md544 Scer\GAL4^hh-Gal4 smo^GD577 smo^{SD123.Scer\UAS.T:Avic\GFP-CFP} Su(fu)^GD11802
Constructs (9)
	P{GD577} P{GD11802} P{UAS-G-iα65A.Q205L} P{UAS-Gprk2.C} P{UAS-G-sα60A.Q215L} P{UAS-PKA.mC} P{UAS-Pka-R1.BGD} P{UAS-ptc.J} P{UAS-smo.CFP.SD123}
Genes (16)
	ci cos en fu Gprk2 Gαi Gαs hh kn Mmus\Pkaca Pka-C1 Pka-R1 ptc Scer\GAL4 smo Su(fu)
Insertions (2)
	P{GAL4}hh^Gal4 P{GawB}ap^md544