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Hedgehog Pathway Diagram / Movie


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#1 Hedgehog

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Posted 30 June 2008 - 04:34 PM


The Hedgehog signaling pathway — named after its polypeptide ligand first identified in fruit flies — plays a key role in the control of cell differentiation, growth, and proliferation. The pathway is most active during embryogenesis but may also play a role in the regulation of adult stem cells involved in the maintenance and regeneration of adult tissues.

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(Click on image do download WMV from http://www.biooncolo...dgehog/index.m)


Two key receptors that appear to be involved in the Hedgehog pathway in normal adult cells are Smoothened, which initiates a signaling cascade, and Patched, which inhibits this signaling mechanism potentially by preventing Smoothened from reaching the cell surface, and thus may function as a tumor suppressor.28,29,38,39 Binding of the Hedgehog ligand to Patched initiates its internalization, allowing Smoothened to move to the surface of the cell and initiates signaling following translocation to the cilium.28,30

When Patched is mutated, constitutive signaling via Smoothened may lead to uncontrolled cell proliferation.32 Some cancer cells may also activate the pathway by mutations in Smoothened or overcome the inhibitory effects of Patched by overexpressing the Hedgehog ligand(s).29,33-35,40

Aberrant activation of this pathway has been implicated in the genesis and progression of a number of human cancers, including basal cell carcinoma and medulloblastoma, making it a potential target for therapeutic intervention.28-31





Hedgehog Pathway Antagonists
The Hedgehog signaling pathway is the subject of ongoing investigation by researchers around the world, including those at Genentech. Emerging preclinical evidence suggests that cell proliferation occurring as a result of Hedgehog signaling can be inhibited by blocking key components of the pathway, such as Smoothened.32-37

Genentech BioOncology is currently investigating a range of small-molecule antagonists of the Hedgehog signaling pathway. This research continues to enhance our understanding of the mechanisms of tumor cell differentiation, growth, and proliferation.


Journal Articles
  • Ingham PW and McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059-3087.
  • Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324-331.
  • Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov. 2006;5:1026-1033.
  • Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutation of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841-851.
  • Johnson RL, Rothman AL, Xie J, et al. Human homolog of Patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668-1671.
  • Romer J, Curran T. Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res. 2005;65:4975-4978.
  • Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB. Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003;442:313-317.
  • Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846-851.
  • Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425:851-856.
  • Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signaling in prostate regeneration, neoplasia, and metastasis. Nature. 2004;431:707-712.
  • Frank-Kamenetsky M, Zhang XM, Bottega S, et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol. 2002;1:10.
  • Romer JT, Kimura H, Magdaleno S, et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc 1+/-p53-/- mice. Cancer Cell. 2004;6:229-240.
  • Denef N, Neubuser D, Perez L, Cohen SM. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell. 2000;102:521-531.
  • Stone DM, Hynes M, Armanini M, et al. The tumour suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996;384:129-134.
  • Xie J, Murone M, Luoh SM, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90-92.






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