Báo cáo sinh học: Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists.

Tuyển tập các báo cáo nghiên cứu về sinh học được đăng trên tạp chí sinh học Journal of Biology đề tài: Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists...
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Báo cáo sinh học: "Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists." Journal BioMed Central of BiologyResearch articleSmall-molecule modulators of Hedgehog signaling: identificationand characterization of Smoothened agonists and antagonistsMaria Frank-Kamenetsky*, Xiaoyan M Zhang*, Steve Bottega*, OivinGuicherit*, Hynek Wichterle†, Henryk Dudek*, David Bumcrot*, Frank YWang*, Simon Jones*, Janine Shulok*, Lee L Rubin* and Jeffery A Porter*Addresses: *Curis, Inc., 61 Moulton Street, Cambridge, MA 02138, USA. †Columbia University, College of Physicians and Surgeons,701 West 168 Street, New York, NY 10032, USA.Correspondence: Jeffery A Porter. E-mail: jporter@curis.comPublished: 6 November 2002 Received: 23 July 2002 Revised: 18 September 2002Journal of Biology 2002, 1:10 Accepted: 11 October 2002The electronic version of this article is the complete one and can befound online at http://jbiol.com/content/1/2/10© 2002 Frank-Kamenetsky et al., licensee BioMed Central LtdISSN 1475–4924 Abstract Background: The Hedgehog (Hh) signaling pathway is vital to animal development as it mediates the differentiation of multiple cell types during embryogenesis. In adults, Hh signaling can be activated to facilitate tissue maintenance and repair. Moreover, stimulation of the Hh pathway has shown therapeutic efficacy in models of Parkinson’s disease and diabetic neuropathy. The underlying mechanisms of Hh signal transduction remain obscure, however: little is known about the communication between the pathway suppressor Patched (Ptc), a multipass transmembrane protein that directly binds Hh, and the pathway activator Smoothened (Smo), a protein that is related to G-protein-coupled receptors and is capable of constitutive activation in the absence of Ptc. Results: We have identified and characterized a synthetic non-peptidyl small molecule, Hh-Ag, that acts as an agonist of the Hh pathway. This Hh agonist promotes cell-type-specific proliferation and concentration-dependent differentiation in vitro, while in utero it rescues aspects of the Hh-signaling defect in Sonic hedgehog-null, but not Smo-null, mouse embryos. Biochemical studies with Hh-Ag, the Hh-signaling antagonist cyclopamine, and a novel Hh- signaling inhibitor Cur61414, reveal that the action of all these compounds is independent of Hh-protein ligand and of the Hh receptor Ptc, as each binds directly to Smo. Conclusions: Smo can have its activity modulated directly by synthetic small molecules. These studies raise the possibility that Hh signaling may be regulated by endogenous small molecules in vivo and provide potent compounds with which to test the therapeutic value of activating the Hh-signaling pathway in the treatment of traumatic and chronic degenerative conditions. Journal of Biology 2002, 1:1010.2 Journal of Biology 2002, Volume 1, Issue 2, Article 10 Frank-Kamenetsky et al. http://jbiol.com/content/1/2/10 Background twelve-pass transmembrane protein that resembles a The hedgehog (hh) gene was identified two decades ago in channel or transporter. Consistent with its role as an essen- Drosophila as a critical regulator of cell-fate determination tial pathway inhibitor, removal of Ptc renders the Hh during embryogenesis [1]. Subsequent work in several model pathway constitutively ‘on’, independent of the Hh ligand. systems has defined and characterized the Hh gene family Similarly, specific point mutations in the transmembrane that encodes highly conserved secreted signaling proteins (for helices of Smo are capable of constitutively stimulating the review see [2]). Hedgehog (Hh) proteins are synthesized as pathway, effectively bypassing Ptc inhibition [3]. At present, approximately 45 kDa precursors that autoprocess in an a controversy surrounds the mechanism by which Ptc ...