Figure 1. The hedgehog signalling pathway. A: Synthesis, secretion and transport of the hedgehog protein (Hh). Hedgehog production: after transcription of Hh in the nucleus and translation of Hh on the endoplasmic reticulum (ER) membrane, Hh is processed both in the ER and the Golgi apparatus. This processing includes the autoproteolytic cleavage of the C-terminal domain, Hh palmitoylation and addition of cholesterol. The palmitoylation of Hh is necessary for efficient hedgehog signalling and cholesterol addition is needed for the Hh oligomerisation, but result in a highly hydrophobic protein. Hence Hh release has to be an active process and this is mediated via the Dispatched (Disp) receptor. The thus-released hydrophobicbic Hh proteins can be then transported in three ways towards their target tissues: (i) In lipid-based particles, (ii) carried by lipophorins of plasma lipoproteins and (iii) via so-called nodal vesicular parcels. The relative importance of these modes or whether other transport modalities exist remains unclear but represents an important question in the field. The Dispatched encodes a 12-TM domain protein (D12) containing a sterol-sensing domain (SSD). B: The hedgehog signalling system in the absence of Hh. When Hh is not present, the Hh receptor Ptc is constitutively active and inactivates Smo. This possibly occurs via its sequestration and degradation by the intracellular endosome and inhibition of Smo translocation to the plasma membrane surface in a mechanism which possibly involves the Ptc-mediated translocation of a 3-β-hydroxysterol over the membrane. In the absence of Hh, Cos2, Fu, Ci-155 are complexed to SuFu and the microtubule skeleton. A number of kinases including PKA, CK1, and GSK3 are recruited by Cos2 to this complex and phosphorylate Ci. This phosphorylation targets Ci for ubiquitination and partial degradation via the SCF complex. A 75-kb cleaved fragment form of Ci (Ci-75) or Gli, however, translocate to the nucleus where it act as a transcriptional repressor for Hh target genes. C: Hh reception: Hh ligand forms a complex with the Ptc receptor as well as with co-receptors like iHog or Boi. This complex is then internalised, thus removing the inhibitory action of patched or Smo, possibly mediated by a translocation of Smo from intracellular vesicles to the plasma membrane and hyperphosphorylation of Smo. Smo subsequently recruits Fu and Cos 2 to the membrane, where these proteins become phosphorylated. In turn this results in the detachment of Fu from Cos 2, relieving Ci from otherwise constitutive phosphorylation, preventing partial proteolysis and accumulation of the intact 155-kb fragment of Ci transcription factor or Gli (1–3), which upon translocation to the nucleus activates transcription of the Hh target genes. Hh, hedgehog; P, phosphate group; Ub, ubiquitination; A, activator; R, repressor; FL, full-length; red arrows, inhibitory effect; Smo7TM, 7-pass transmembrane spanning Smoothened receptor; Ptc12TM, 12-pass transmembrane receptor patched; SSD, sterol-sensing domain. Red receptors refers to activated receptors (e.g. Smo at the membrane surface); yellow receptors refers to inactivated receptors (e.g. Ptc); Ihog, interference hedgehog co-receptor; Boi, brother of Ihog; Ci, Cubitus interruptus; Ci-155 A, 155-kb intact active form of Ci; Ci-75 R, 75-kb cleaved form of Ci; Cos2, Costal2 (atypical kinesin-like protein); Fu, fused (a putative serine/threonine kinase); Su(fu), suppressor of fused (PEST domain protein); PKA, protein kinase A; CKI, casein kinase I; GSK3, glycogen synthase kinase.
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