Hedgehog Signaling Pathway
Overview of The Hedgehog Signaling Pathway:
The morphogen Hedgehog is an autoproteolytic secreted protein that activates an essential cellular pathway (Hedgehog Signaling Pathway) required during the embryogenesis of various organisms. The pathway is involved in cell fate determination, pattern formation, proliferation, and differentiation in multiple tissue types. Its fundamental importance is exemplified by the many mutations that cause severe developmental defects as well as the many types of cancers that result from mis- activation.
The prevailing model for Hh pathway activation in cells is based on both biochemical and genetic studies in Drosophila and vertebrates (Ingham and McMahon, 2001; Lum and Beachy, 2004). Pathway regulation in cells can be described as a two state model; in the absence or presence of Hh. In the absence of Hh, Patched (ptc), 12 transmembrane spanning protein (Hooper and Scott, 1989; Lum and Beachy, 2004), prevents Smoothened (smo), a 7 transmembrane spanning protein with homology to G-protein coupled receptors (Alcedo et. al.1996; Lum and Beachy, 2004) from activating down stream components. Upon Hh reception, inhibition of smo by ptc is released leading to activation of the pathway (Lum and Beachy, 2004). The response triggered by Hh involves key cytoplasmic effectors including: Costal-2 (cos2) a kinesin-related microtubule binding protein (Robbins et al., 1997; Sisson et al., 1997), Fused (Fu), a putative serine/threonine kinase (Therond et al., 1996), and a transcription factor Cubitus interruptus (Ci). Hh signaling 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). This converts Ci from a transcriptional repressor to an activator leading to target gene activation in cells receiving Hh (Aza-Blanc et al., 1997).
Hh proteins reveals unique post-translational modifications necessary to process the active form. In order for Hh to be an active secreted signaling molecule it must go through three processing events: auto-cleavage generating an N-terminal fragment (HhNp), the addition of cholesterol, and the addition of palmitic acid( Porter et al., 1996; Pepinsky et al., 1998). At the point of cleavage on the C-terminus of HhNp there is a covalent attachment of cholesterol (Porter et al. 1996). In addition, palmitic acid is attached to the N-terminus of HhNp by a possible acyltransferase, Rasp/skinny hedgehog(ski) (Chamoun et al., 2001; Lee and Treisman, 2001;Amanai and Jiang, 2001; Micchelli et al., 2002). Thus it is thought that the addition of lipids, cholesterol and palmitic acid, restricts Hh's ability to move freely in the extra-cellular environment (Zeng et al.,2001; Gallet et. al., 2003; Chen et al. 2004;).
The release of Hh from cells also requires a multiple-pass, transmembrane transport-like protein, Dispatched (Disp). (Burke et al., 1999; Caspary et al., 2002; Kawakami et al., 2002; Nakano et. al. 2004). Disp shares significant sequence similarity with Ptc, particularly in a region implicated in lipid transport or secretion of lipid modified proteins (Lum and Beachy, 2004). In the absence of Disp, cholesterol-modified Hh is not secreted from cells (Burke et al., 1999).
There is also recent demonstration of an important role for extracellular matrix proteins outside the cell in Hh signaling. Heparan sulphate proteoglycans (HSPG) consist of a protein core which can be a syndecan or glypican, on which HSPG chains are linked (Tabata and Takei, 2004). These include the Drosophila homologs of the mammalian EXT tumor suppressor gene family Tout velu (Ttv), brother of ttv (botv) and sister of tout velu (sotv) (Bellaiche et al., 1998; The et al., 1999; McCormick et al., 1998; Lind et al., 1998; Han et. al. 2004a,b; Bornemann et al. 2004; Takei et al. 2004) division abnormally delayed (dally) and dally-like (dly) (Nakato et al., 1995; Baeg et al., 2001; Khare and Baumgartner, 2000; Desbordes and Sanson, 2003; Lum et al. 2003), and Sugarless (sgl) and sulfateless(sfl) (Lin et. al. 1999, Baeg et al., 2001; The et al., 1999).
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