PMID- 10477300
OWN - NLM
STAT- MEDLINE
DCOM- 19991104
LR  - 20220215
IS  - 0950-1991 (Print)
IS  - 0950-1991 (Linking)
VI  - 126
IP  - 19
DP  - 1999 Oct
TI  - Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by
      protein kinase A.
PG  - 4331-9
AB  - The Hedgehog signal transduction pathway is involved in diverse patterning events
      in many organisms. In Drosophila, Hedgehog signaling regulates transcription of
      target genes by modifying the activity of the DNA-binding protein Cubitus
      interruptus (Ci). Hedgehog signaling inhibits proteolytic cleavage of full-length
      Ci (Ci-155) to Ci-75, a form that represses some target genes, and also converts 
      the full-length form to a potent transcriptional activator. Reduction of protein 
      kinase A (PKA) activity also leads to accumulation of full-length Ci and to
      ectopic expression of Hedgehog target genes, prompting the hypothesis that PKA
      might normally promote cleavage to Ci-75 by directly phosphorylating Ci-155. Here
      we show that a mutant form of Ci lacking five potential PKA phosphorylation sites
      (Ci5m) is not detectably cleaved to Ci-75 in Drosophila embryos. Moreover,
      changes in PKA activity dramatically altered levels of full-length wild-type Ci
      in embryos and imaginal discs, but did not significantly alter full-length Ci5m
      levels. We corroborate these results by showing that Ci5m is more active than
      wild-type Ci at inducing ectopic transcription of the Hh target gene wingless in 
      embryos and that inhibition of PKA enhances induction of wingless by wild-type Ci
      but not by Ci5m. We therefore propose that PKA phosphorylation of Ci is required 
      for the proteolysis of Ci-155 to Ci-75 in vivo. We also show that the activity of
      Ci5m remains Hedgehog responsive if expressed at low levels, providing further
      evidence that the full-length form of Ci undergoes a Hedgehog-dependent
      activation step.
FAU - Price, M A
AU  - Price MA
AD  - Department of Biological Sciences, Columbia University, New York, New York 10027,
      USA.
FAU - Kalderon, D
AU  - Kalderon D
LA  - eng
GR  - GM41815/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Development
JT  - Development (Cambridge, England)
JID - 8701744
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Insect Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (ci protein, Drosophila)
RN  - 149291-21-4 (hh protein, Drosophila)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Cyclic AMP-Dependent Protein Kinases/antagonists &
      inhibitors/*metabolism/pharmacology
MH  - DNA-Binding Proteins/*metabolism
MH  - Drosophila/embryology/*metabolism
MH  - *Drosophila Proteins
MH  - Embryo, Nonmammalian/metabolism
MH  - Hedgehog Proteins
MH  - Insect Proteins/genetics/metabolism
MH  - Models, Genetic
MH  - Molecular Sequence Data
MH  - Mutagenesis
MH  - Phosphorylation
MH  - Recombinant Proteins/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Transcription Factors
MH  - Transcription, Genetic
MH  - Wings, Animal/embryology
EDAT- 1999/09/08 00:00
MHDA- 1999/09/08 00:01
CRDT- 1999/09/08 00:00
PHST- 1999/09/08 00:00 [pubmed]
PHST- 1999/09/08 00:01 [medline]
PHST- 1999/09/08 00:00 [entrez]
AID - 10.1242/dev.126.19.4331 [doi]
PST - ppublish
SO  - Development. 1999 Oct;126(19):4331-9. doi: 10.1242/dev.126.19.4331.