Document Detail

Role of lipid metabolism in smoothened derepression in hedgehog signaling.
MedLine Citation:
PMID:  20643350     Owner:  NLM     Status:  MEDLINE    
The binding of Hedgehog (Hh) to its receptor Patched causes derepression of Smoothened (Smo), resulting in the activation of the Hh pathway. Here, we show that Smo activation is dependent on the levels of the phospholipid phosphatidylinositol-4 phosphate (PI4P). Loss of STT4 kinase, which is required for the generation of PI4P, exhibits hh loss-of-function phenotypes, whereas loss of Sac1 phosphatase, which is required for the degradation of PI4P, results in hh gain-of-function phenotypes in multiple settings during Drosophila development. Furthermore, loss of Ptc function, which results in the activation of Hh pathway, also causes an increase in PI4P levels. Sac1 functions downstream of STT4 and Ptc in the regulation of Smo membrane localization and Hh pathway activation. Taken together, our results suggest a model in which Ptc directly or indirectly functions to suppress the accumulation of PI4P. Binding of Hh to Ptc derepresses the levels of PI4P, which, in turn, promotes Smo activation.
Amir Yavari; Raghavendra Nagaraj; Edward Owusu-Ansah; Andrew Folick; Kathy Ngo; Tyler Hillman; Gerald Call; Rajat Rohatgi; Matthew P Scott; Utpal Banerjee
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Developmental cell     Volume:  19     ISSN:  1878-1551     ISO Abbreviation:  Dev. Cell     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-20     Completed Date:  2010-08-30     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  101120028     Medline TA:  Dev Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  54-65     Citation Subset:  IM    
Copyright Information:
(c) 2010 Elsevier Inc. All rights reserved.
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MeSH Terms
1-Phosphatidylinositol 4-Kinase / genetics,  metabolism
Animals, Genetically Modified
Caspase 3 / metabolism
Drosophila / genetics*,  growth & development,  metabolism*
Drosophila Proteins / genetics*,  metabolism*
Eye / growth & development,  metabolism
Genes, Insect
Hedgehog Proteins / genetics*,  metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
Lipid Metabolism*
Phosphatidylinositol Phosphates / metabolism
Phosphoric Monoester Hydrolases / genetics,  metabolism
Receptors, Cell Surface / genetics,  metabolism
Receptors, G-Protein-Coupled / genetics*,  metabolism*
Signal Transduction
Wnt1 Protein / metabolism
Grant Support
R01 EY008152/EY/NEI NIH HHS; R01 EY008152-22/EY/NEI NIH HHS; R01 HL067395/HL/NHLBI NIH HHS; R01 HL067395-09/HL/NHLBI NIH HHS; R01EY008152/EY/NEI NIH HHS; R01HL067395/HL/NHLBI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Drosophila Proteins; 0/Hedgehog Proteins; 0/Phosphatidylinositol Phosphates; 0/Receptors, Cell Surface; 0/Receptors, G-Protein-Coupled; 0/Wnt1 Protein; 0/dpp protein, Drosophila; 0/phosphatidylinositol 4-phosphate; 0/ptc protein, Drosophila; 0/smoothened protein, Drosophila; 0/wg protein, Drosophila; 149291-21-4/hedgehog protein, Drosophila; EC 4-Kinase; EC Mitogen-Activated Protein Kinases; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.4.22.-/Caspase 3
Comment In:
Dev Cell. 2010 Jul 20;19(1):3-4   [PMID:  20643342 ]

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