Hedgehog signaling pathway (WP1022)

The Hedgehog family of proteins are signaling proteins that are crucial for a number of physiological processes including morphogenesis during development. In adult organisms, it is also involved in the regulation of theca cell development in growing follicles and in regulating the development and function of the somatic cells of the testis. Vertebrates are known to have 3 Hedgehog genes, which show different spatio-temporal expression patterns and perform specialized functions. These are - Desert hedgehog (Dhh), Indian hedgehog (Ihh), and Sonic hedgehog (Shh). The Patched (PTCH) proteins (Patched 1 and Patched 2 - PTCH1 and PTCH2) serve as receptors for the Hedgehog proteins. In the 'off' state, PTCH receptors inhibit the Smo protein by mechanism(s) which are still not understood completely. In this state, the Gli2/3 Zn-finger transcription factors are phosphorylated and processed in a proteasome-dependent manner to generate a transcriptionally repressor form. SUFU, a cytoplasmic protein, was also found to interact with all the three Gli proteins resulting in the repression of its transcriptional activity. In the 'Signaling cell', which is the cell which secretes the Hedgehog proteins, an active ligand is produced following processing of the precursor Hedgehog protein. This processing involves autocleavage by the catalytic domain and bi-lipidation (cholesterol moiety at C-terminus and palmitate at the N-terminus) of the Hedgehog protein. These active ligands travel to the 'responding cell' via interactions with glypicans and megalin. On the responding cell, the active ligand interacts with PATCHED 1 (PTCH1) and PATCHED 2 (PTCH2), which results in the activation and translocation of Smoothed (Smo) to the cilium(plasma membrane in Drosophila). Activation of Smo results in the inhibition of Gli proteolysis and the production of the transcriptional repressor form. This might also promote the formation of the transcription activator form of the protein. The G-protein coupled receptor kinase-2 enhances the association between β-arrestin 2 and Smo probably by phosphorylating Smo. The two proteins also mediates increased internalization of Smo in a clathrin- dependent process and increased Hedgehog signaling. Kif7, a Drosophila Costal2 (Cos2) homolog, is capable of interacting with the Gli proteins and is known to exert positive and negative effects on Hedgehog signaling. The Fused (Fu) homolog, which can form a complex with Kif7, Gli and and SuFu (similar to Drosophila Gli, Cos2, Su and SuFu) may also be involved in the regulation of this pathway. Please access this pathway at [http://www.netpath.org/netslim/hedgehog_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3.

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