Tales of the weary regulated scaffold, Costal2

2004 2004

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Abstract (summary)

Hedgehog (Hh) deficient flies, mice and humans reveal a conserved developmental requirement for Hh signaling, while aberrant Hh signaling causes basal cell carcinoma, medulloblastoma, and is implicated in other tumors including breast, lung and pancreas. We address the poorly understood mechanism of Hh signal transduction from the plasma membrane to the nucleus, taking advantage of the extensive genetic characterization of the Hh pathway in Drosophila melanogaster. The secreted protein Hh binds its receptor Patched (Ptc), relieving Ptc inhibition of the GPCR-like protein, Smoothened (Smo). Downstream of Smo is the microtubule associated Hedgehog Signaling Complex (HSC). The HSC consists of the Kinesin related protein (KRP) Costal2 (Cos2), the serine/threonine protein kinase Fused (Fu) and Cubitus interruptus (Ci), the zinc finger transcription factor that regulates Hh target genes. Cos2 and Fu are required to produce transcriptional repressor and activator forms of Ci. Drosophila genetics suggest that fu, cos2, ci and Suppressor of fused [Su(fu)], which suppresses fu phenotypes, interact in a non linear fashion, and phenotypes of the Drosophila wing suggest two complexes could be involved. However, it is not known how Smo signals to the HSC, nor how this complex that tethers Ci from the nucleus, also serves to activate Ci. We demonstrate that Su(fu) associates with the HSC, however, Su(fu) does not appear to bind the microtubule associated complex, and the HSC is stable in the absence of Su(fu). While Ci accumulates in the nucleus of cells exposed to Hh, we show that other HSC members and Su(fu) do not. Cos2 tethers the HSC to vesicular membranes, and releases membranes in response to Hh. Cos2 also binds Smo, although with lower affinity than membranes and with no Hh sensitivity. Additionally, the bulk of Cos2 membrane association is Smo independent. We have thus provided biochemical evidence for two HSC complexes, targeted by Cos2 to Smo or membranes. Differential regulation of these two complexes can explain observations that Ci repressor and Ci activator formation occur with different kinetics. We conclude that Cos2 is a regulated and versatile scaffold that functions by providing the localization required for both types of Ci processing.

Indexing (details)

0487: Biochemistry
Identifier / keyword
Pure sciences; Cancer; Costal2; Hedgehog; Scaffold
Tales of the weary regulated scaffold, Costal2
Stegman, Melanie A.
Number of pages
Publication year
Degree date
School code
DAI-B 66/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780496929481, 0496929488
Robbins, David J.
University of Cincinnati
University location
United States -- Ohio
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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