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Drosophila Hh Signalling pathway

Summary: 

Processing of HH ligand The precursor of HH is auto-catalytically cleaved to produce an N-terminal (HH-N) and a C- terminal (HH-C) fragments ([1]; [2]). A cholesterol moiety is covalently attached to the last amino acid of HH-N to create HH-Np, that is responsible for the biological activities of HH proteins ([1]; [2]; [3]). The N-terminal region of HH-Np is further modified by addition of palmitate that is essential for its signalling activity ([4]; [5]; [6]; [7]; [8]; [9]). We model these aspects by an AND rule (combining inputs from DLP, IHOG, Rasp, DISP, SHF, Lipophorin, BOI and DALLY) attached to the component representing the secreted HH molecule, denoted Hh in our model. HH Signalling Two integral membrane proteins are involved in HH signal reception: Patched and Smoothened. HH binding to its receptor Patched (PTC) relieves PTC-mediated repression of Smoothened (SMO), a serpentine-like membrane protein required for HH signalling ([10]; [11]). This allows SMO stabilisation, activation, and phosphorylation by Shaggy (SGG), and downstream signalling through the formation of a protein complex including the serine threonine kinase Fused (FU), the kinesin-like protein Costa (COS), and the protein Suppressor of Fused (SU(FU)), ultimately controlling the post-translational processing of the protein Cubitus interruptus (CI) ([12]). In the absence of HH, COS binds CI directly and sequesters it in the cytoplasm with the help of SUFU. The recruitment of different kinases (Casein kinase 1 alpha, Shaggy, Protein kinase A) then leads to the phosphorylation of CI and to its proteolysis by SLMB. The resulting truncated protein (CI_rep) is released and enters the nucleus, where it has a transcriptional repressing activity. Recent evidence further indicates that SMO is inhibited by TOW, which tentatively mediates the effect of PTC on SMO ([13]; [14]). Following SMO activation, the transcription factor CI is phosphorylated and translocated into the nucleus in its entire form, which plays a transcriptional activatory role (CI_act). In the model, a cascade of inhibitions, from HH on PTC, and from PTC on SMO, implements the indirect positive action of HH on SMO. A protein complex including CI, COS, and FU, phosphorylates and thereby inhibits SU(FU), ultimately favouring the CI activatory form and its translocation into the nucleus. We model the roles of the kinases (SGG, PKA, and CK1a), COS and SU(FU) (both needed to recruit the kinases) in the processing of CI in terms of inhibitory interactions on CI_act and activatory interactions on CI_rep ([15]; [16]). Complexes are represented implicitly (they are formed as soon as the components are synthesised or activated), while logical rules define component activity requirements to form CI_act versus CI_rep forms. To explore the dynamic of the pathway, we define two initial states to simulate the presence and the absence of signalling. On one hand, the non binding of HH (level expression 0) triggers a series of signalling cascades that lead to the activation of several kinases (for example SGG, PKA, CK1a, ...) at level of expression 1, which will permit the formation of CI repressor (expressed at level 1), which in turn will inhibit the targets. On the other hand, the presence of HH (level of expression 1) leads to a stable state corresponding to the signalling conditions leading to the formation of CI activator that will activate the targets node (level of expression 1).


References

  1. Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA.  1994.  Autoproteolysis in hedgehog protein biogenesis.. Science (New York, N.Y.). 266(5190):1528-37.
  2. Porter JA, Young KE, Beachy PA.  1996.  Cholesterol modification of hedgehog signaling proteins in animal development.. Science (New York, N.Y.). 274(5285):255-9.
  3. Ingham PW, McMahon AP.  2001.  Hedgehog signaling in animal development: paradigms and principles.. Genes & development. 15(23):3059-87.
  4. Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K et al..  1998.  Identification of a palmitic acid-modified form of human Sonic hedgehog.. The Journal of biological chemistry. 273(22):14037-45.
  5. Wang G, Amanai K, Wang B, Jiang J.  2000.  Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus.. Genes & development. 14(22):2893-905.
  6. Amanai K, Jiang J.  2001.  Distinct roles of Central missing and Dispatched in sending the Hedgehog signal.. Development (Cambridge, England). 128(24):5119-27.
  7. Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K.  2001.  Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.. Science (New York, N.Y.). 293(5537):2080-4.
  8. Lee JD, Treisman JE.  2001.  The role of Wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc.. Development (Cambridge, England). 128(9):1519-29.
  9. Micchelli CA, The I, Selva E, Mogila V, Perrimon N.  2002.  Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling.. Development (Cambridge, England). 129(4):843-51.
  10. Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper JE.  1996.  The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal.. Cell. 86(2):221-32.
  11. Chen Y, Struhl G.  1996.  Dual roles for patched in sequestering and transducing Hedgehog.. Cell. 87(3):553-63.
  12. Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M, Beachy PA.  2003.  Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells.. Science (New York, N.Y.). 299(5615):2039-45.
  13. Ayers KL, Rodriguez R, Gallet A, Ruel L, Thérond P.  2009.  Tow (Target of Wingless), a novel repressor of the Hedgehog pathway in Drosophila.. Developmental biology. 329(2):280-93.
  14. Ayers KL, Thérond PP.  2010.  Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling.. Trends in cell biology. 20(5):287-98.
  15. Aikin RA, Ayers KL, Thérond PP.  2008.  The role of kinases in the Hedgehog signalling pathway.. EMBO reports. 9(4):330-6.
  16. Wilson CW, Chuang P-T.  2006.  New "hogs" in Hedgehog transport and signal reception.. Cell. 125(3):435-8.
Curation
Submitter: 
Abibatou MBODJ and Denis THIEFFRY


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