Hedgehog Signaling Pathway Database
 
Hedgehog Pathway Models

Hh Signal Transduction | Formation of Active Hh Protein

 

In the absence of Hh, Patched (ptc) prevents Smoothened (smo) from activating down stream components. Ptc is a 12 transmembrane spanning protein with a sterol sensing domain (Hooper and Scott, 1989; Lum and Beachy, 2004). Smo is a 7 transmembrane spanning protein with homology to G-protein coupled receptors (Alcedo et. al.1996; Lum and Beachy, 2004). It has not been determined mechanisticly how Ptc prevents Smo from activating the Hh pathway. A complex of several key cytoplasmic effectors has been noted. These include: Costal-2 (cos2) a kinesin-related microtubule binding protein (Robbins et al., 1997; Sisson et al., 1997; Lum et al. 2003; Zhang et al., 2005), Fused (Fu), a putative serine/threonine kinase (Therond et al., 1996), Supressor of fused (Sufu), a scafold protein (Pham et. al., 1995; Chen et al., 1999) and a transcription factor Cubitus interruptus (Ci) (Aza-Blanc et al., 1997; Chen et al., 1999).Minimal phosphorylation of both Fu and Cos2 in the absence of Hh has been noted (Ogden et. al.,2004).

 

Full length Ci 155 is phosphorylated by various kinases (Caesin kinase I (Ck1), Glycogen syntase kinase 3 (GSK3), and Protein kinase A (PKA) (Price and Kalderon, 2002; Zhang et al., 2005). Phosphorylation of Ci leads to cleavage and ubiquitination (Price and Kalderon, 2002; Zhang et al., 2005).

 

Ci75, a truncated form of Ci, moves into the nucleus and functions as a repressor (Aza-Blanc et al., 1997; Chen et al., 1999).

 

Upon Hh reception, inhibition of smo by ptc is released by some unknown mechanism leading to activation of the pathway (Lum and Beachy,2004).

 

Smo has been shown to be phosphoryated by G-protein coupled receptor kinase 2 (Grk2) (Chen et. al., 2004; Ogden et. al.,2004).

 

A phosphorylated form of Smo attracts beta Arrestin 2 (bArrb2) and the formation of a clathrin coated pit for internalization (Chen et. al., 2004). Cos2 associates with phosphorylated smo. Cos2 forms a scafold on which a complex of Fu, Ci, and Sufu (Lum et al., 2003) associates. Reception of Hh also converts Fu to a hyperphosphorylated form, (Therond et al.,1996; Ramirez-Weber et al., 2000; Stegman et al. 2001) leading to inhibition of Ci proteolysis (Aza- Blanc et al., 1997; Price and Kalderon, 2002; Zhang et al., 2005).

 

This converts Ci from a transcriptional repressor to an activator leading to target gene activation in cells receiving Hh (Aza-Blanc et al., 1997; Price and Kalderon, 2002; Zhang et al., 2005). More recently Intraflagelar trafficking Proteins (Ift 172 and Ift 88) have been shown to be assocatiated with Smo, Cos2, Fu, Ci, and SuFu in mammalian cilia (Corbit et al., 2005; Huangfu et al., 2003; Huangfu and Anderson, 2005; Liu et al, 2005).

 

Bibliography:

Aza-Blanc P, Ramirez-Weber FA, Laget MP, Schwartz C, Kornberg TB. (1997) Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89(7):1043-53.

Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. (2005) Vertebrate Smoothened functions at the primary cilium. Nature. 437(7061):1018-21..

Chen CH, von Kessler DP, Park W, Wang B, Ma Y, Beachy PA. (1999) Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98(3):305-16.

Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F,Lefkowitz RJ. (2004) Activity-dependent internalization of smoothened mediated by beta- arrestin 2 and GRK2. Science. 306(5705):2257-60.

Hooper, J.E., and Scott, M.P. (1989). The Drosophila patched gene encodes a putative membrane protein required for segmental patterning. Cell 59: 751-765.

Ingham, P. W. and McMahon, A. P. (2001). Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059-3087.

Lum, L. and Beachy,P.A. (2004) Hedgehog response network: sensors, switches, and routers. Science 304: 1755-1789.

Lum L, Zhang C, Oh S, Mann RK, von Kessler DP, Taipale J, Weis-Garcia F,Gong R, Wang B, Beachy PA. (2003) Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell.;12(5):1261-74.

Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV. (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature. 426(6962):83-7.

Huangfu D, Anderson KV. (2005) Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 9;102(32):11325-30.

Liu A, Wang B, Niswander LA. (2005) Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 132(13):3103-11.

Pham A, Therond P, Alves G, Tournier FB, Busson D, Lamour-Isnard C, Bouchon BL, Preat T, Tricoire H. (1995) The Suppressor of fused gene encodes a novel PEST protein involved in Drosophila segment polarity establishment. Genetics. 140(2): 587-98.

Price MA, Kalderon D. (2002) Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell. 22;108(6):823-35.

Ogden SK, Ascano M Jr, Stegman MA, Robbins DJ. (2004) Regulation of Hedgehog signaling: a complex story. Biochem Pharmacol. 67(5):805-14.

Ramirez-Weber FA, Casso DJ, Aza-Blanc P, Tabata T, Kornberg TB. (2000) Hedgehog signal transduction in the posterior compartment of the Drosophila wing imaginal disc. Mol Cell. 6(2):479-85.

Sisson, J.C., Ho, K.S., Suyama, K., and Scott, M.P. (1997). Costal2,a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90: 235-245.

Stegman MA, Vallance JE, Elangovan G, Sosinski J, Cheng Y, Robbins DJ. (2000) Identification of a tetrameric hedgehog signaling complex. J Biol Chem. 21;275 (29):21809-12.

Therond, P.P., Knight, J.D., Kornberg, T.B., and Bishop, J.M. (1996). Phosphorylation of the fused protein kinase in response to signaling from hedgehog. Proc. Natl. Acad. Sci. USA 93: 4224-4228.

Zhang W, Zhao Y, Tong C, Wang G, Wang B, Jia J, Jiang J. (2005) Hedgehog- regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev Cell. 8(2):267-78.



Last updated 28-Aug-2006

home page | about Hedgehog | gene index

© Copyright 2006