Drosophila Hh Signalling pathway

Taxon: D. melanogaster
Process: Signalling
Submitter: Abibatou MBODJ and Denis THIEFFRY

Supporting paper: Mbodj, Abibatou and Junion, Guillaume and Brun, Christine and Furlong, Eileen E. M. and Thieffry, Denis (2013). Logical modelling of Drosophila signalling pathways. Molecular BioSystems. 10.1039/c3mb70187e

Model file(s) Description(s)
Hh__Pathway_11Jun2013.zginml GINsim file for Drosophila Hh Signalling pathway
Hh_Pathway_Documentation_11May013.pdf Drosophila Hh Signalling pathway model documentation

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 (SUFU), 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).

  1. J. Lee, S. Ekker, D. von Kessler, J. Porter, B. Sun, and P. Beachy. Autoproteolysis in hedgehog protein biogenesis. Science, 266(5190):1528–1537, December 1994. doi:10.1126/science.7985023. ↩↩

  2. Jeffery A. Porter, Keith E. Young, and Philip A. Beachy. Cholesterol modification of hedgehog signaling proteins in animal development. Science, 274(5285):255–259, October 1996. doi:10.1126/science.274.5285.255. ↩↩

  3. Philip W. Ingham and Andrew P. McMahon. Hedgehog signaling in animal development: paradigms and principles. Genes & Development, 15(23):3059–3087, December 2001. doi:10.1101/gad.938601. ↩

  4. R. Blake Pepinsky, Chenhui Zeng, Dingyi Wen, Paul Rayhorn, Darren P. Baker, Kevin P. Williams, Sarah A. Bixler, Christine M. Ambrose, Ellen A. Garber, Konrad Miatkowski, Frederick R. Taylor, Elizabeth A. Wang, and Alphonse Galdes. Identification of a palmitic acid-modified form of human sonic hedgehog. Journal of Biological Chemistry, 273(22):14037–14045, May 1998. doi:10.1074/jbc.273.22.14037. ↩

  5. Gelin Wang, Kazuhito Amanai, Bing Wang, and Jin Jiang. Interactions with costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes & Development, 14(22):2893–2905, November 2000. doi:10.1101/gad.843900. ↩

  6. Kazuhito Amanai and Jin Jiang. Distinct roles of central missing and dispatched in sending the hedgehog signal. Development, 128(24):5119–5127, December 2001. doi:10.1242/dev.128.24.5119. ↩

  7. Zeina Chamoun, Randall K. Mann, Denise Nellen, Doris P. von Kessler, Manolo Bellotto, Philip A. Beachy, and Konrad Basler. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science, 293(5537):2080–2084, September 2001. doi:10.1126/science.1064437. ↩

  8. Jeffrey D. Lee and Jessica E. Treisman. The role of wingless signaling in establishing the anteroposterior and dorsoventral axes of the eye disc. Development, 128(9):1519–1529, May 2001. doi:10.1242/dev.128.9.1519. ↩

  9. Craig A. Micchelli, Inge The, Erica Selva, Vladic Mogila, and Norbert Perrimon. Rasp, a putative transmembrane acyltransferase, is required for hedgehog signaling. Development, 129(4):843–851, February 2002. doi:10.1242/dev.129.4.843. ↩

  10. Joy Alcedo, Marina Ayzenzon, Tonia Von Ohlen, Markus Noll, and Joan E Hooper. The drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell, 86(2):221–232, July 1996. doi:10.1016/s0092-8674(00)80094-x. ↩

  11. Yu Chen and Gary Struhl. Dual roles for patched in sequestering and transducing hedgehog. Cell, 87(3):553–563, November 1996. doi:10.1016/s0092-8674(00)81374-4. ↩

  12. Lawrence Lum, Shenqin Yao, Brian Mozer, Alessandra Rovescalli, Doris Von Kessler, Marshall Nirenberg, and Philip A. Beachy. Identification of hedgehog pathway components by rnai in drosophila cultured cells. Science, 299(5615):2039–2045, March 2003. doi:10.1126/science.1081403. ↩

  13. Katie L. Ayers, Ralph Rodriguez, Armel Gallet, Laurent Ruel, and Pascal Thérond. Tow (target of wingless), a novel repressor of the hedgehog pathway in drosophila. Developmental Biology, 329(2):280–293, May 2009. doi:10.1016/j.ydbio.2009.02.037. ↩

  14. Katie L. Ayers and Pascal P. Thérond. Evaluating smoothened as a g-protein-coupled receptor for hedgehog signalling. Trends in Cell Biology, 20(5):287–298, May 2010. doi:10.1016/j.tcb.2010.02.002. ↩

  15. Reid A Aikin, Katie L Ayers, and Pascal P Thérond. The role of kinases in the hedgehog signalling pathway. EMBO reports, 9(4):330–336, April 2008. doi:10.1038/embor.2008.38. ↩

  16. Christopher W. Wilson and Pao-Tien Chuang. New “hogs” in hedgehog transport and signal reception. Cell, 125(3):435–438, May 2006. doi:10.1016/j.cell.2006.04.016. ↩