QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Jia, J. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Jia, J. Social Bookmarking                   What's this?

Fused–Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation

¹ Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA; ² Center for Developmental Biology and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; ³ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA

The seven-transmembrane protein Smoothened (Smo) acts as a signal transducer in the Hedgehog (Hh) pathway that mediates many key developmental processes. In Drosophila, Hh-induced phosphorylation promotes Smo cell-surface accumulation and signaling activity; however, the mechanisms controlling Smo phosphorylation and cell-surface accumulation are still unknown. The intracellular signaling complex containing Fused (Fu) and Costal2 (Cos2) is thought to transduce the Hh signal downstream from Smo. Here, we identify a novel feedback mechanism that regulates Smo through the Fu–Cos2 complex. We found that Hh-induced Smo accumulation is inhibited in fu mutant clones or by expressing a dominant-negative form of Fu, and such inhibition is alleviated by removal of Cos2. Conversely, overexpressing Cos2 blocks Smo accumulation, which is reversed by coexpressing Fu. Cos2 blocks Smo accumulation through its C-terminal Smo-interacting domain, and Fu antagonizes Cos2 by phosphorylating Cos2 at Ser572. Furthermore, we found that Ser572 phosphorylation attenuates the Cos2–Smo interaction and promotes Cos2 instability. Finally, we provided evidence that Fu and Cos2 control Smo cell-surface accumulation by regulating Smo phosphorylation. Our data suggest that Cos2–Smo interaction blocks Hh-induced Smo phosphorylation, and that Fu promotes Smo phosphorylation by antagonizing Cos2.

[Keywords: Smo; Fu; Cos2; Hh; phosphorylation; signal transduction]

Received April 3, 2007; revised version accepted June 18, 2007.

⁵ Corresponding author.

E-MAIL jijia{at}UTMB.edu; FAX (409) 747-1938.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1557407

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. J. Casso, S. Liu, D. D. Iwaki, S. K. Ogden, and T. B. Kornberg A Screen for Modifiers of Hedgehog Signaling in Drosophila melanogaster Identifies swm and mts Genetics, March 1, 2008; 178(3): 1399 - 1413. [Abstract] [Full Text] [PDF]

				L. Jacob and L. Lum Deconstructing the Hedgehog Pathway in Development and Disease Science, October 5, 2007; 318(5847): 66 - 68. [Abstract] [Full Text] [PDF]