& Its Role In Basal Cell Carcinoma Andrew Brown Patched & Its Role In Basal Cell Carcinoma Andrew Brown

Quijada L, Callejo et al. 2013 Patched was first found as part of the Sonic Hedgehog Pathway, acting to suppress . Patched was first discovered in Drosophila melanogaster as part of the Sonic Hedgehog pathway. It was found to play a key role in wing formation, in essence acting to repress wingless of the Wnt pathway. 2 Patched genes have since been discovered in humans, PTCH1 and PTCH 2 that play a role in embryonic development and tissue maintenance and regeneration. 2 large extracellular loops and a sterol-sensing domain are conserved

In the canonical Hedgehog pathway, patched has two primary functions: to transmit the hedgehog signal and modulate the extracellular Hedgehog gradient. The PTCH gene product is a 12-membrane pass receptor. Without signaling, it functions to repress Smoothened, another protein that is active on the membrane. Shh binding to PTCH inhibits its repression of and thus activates Smoothened. Smoothened then goes on to activate the GLI family of transcription factors, which induce transcription of growth factors like TGFβ, WNT, and BMP (Bone morphogenic factors). The pathway also serves as a negative regulator of itself as one of the products is PTCH itself. Quijada et al. 2012

Though the exact mechanism is unknown, when Hh binds Patched, repression of Smoothened is alleviated. The Shh ligand binds to the two large extracellular loops of the Patched protein. Co-immunoprecipitation experiments show this interaction. In vertebrates, patched complexes with other membrane proteins to confer signalling The exact mechanism by which Patched inhibits Smoothened is still unknown. It is known that the two proteins do not directly interact. Localization experiments show that activation of Smoothened by Shh binding to Patched causes the phosphorylation of Smoothened. Smoothened also must relocate to the membrane to be active. Dorsam et al. 2007

In the noncanonical Hedgehog pathway, patched binds cyclin B1 and an apoptosis promoting complex, preventing cell proliferation In the absence of Hh ligands, Patched binds Cyclin B1 and an apoptosis promoting complex (activates). When a Hh ligand binds Patched, Cylcin B1 and the complex are release, and cell proliferation is allowed. This aspect of the pathway is Smoothened independent. Type II noncanonical does not involve Patched. It is a result of Smoothened regulating actin cytoskeleton Robbins et al. 2012

In knockout mice experiments, elimination of Patched leads to embryonic lethality as a result of failure to form the neural tube. In knockout mouse experiments, elimination of Ptc lead to embryonic lethality as a result of failure to form the neural tube. Ptc-/- led to overexpression of Shh and floor plate formation. In other words, Patched is necessary for embryonic development. Goodrich et al. 1997

Mutations in Patched often lead to a truncated gene product, uncontrolled cell proliferation, and basal cell carcinomas. Mutations in the Patched genes that leave the pathway constitutively active lead to tumorigenesis. Mutations can be missense, though many mutations are nonsense or frameshift mutations that can occur in any of the 23 exons and can lead to truncated gene products. The most common skin cancer More than 4 million cases in US each year, close to 50% of Americans who live to age 65 have About 30% lifetime risk of developing some point in life Additional mutations in p53 in about 40% of BCC Some instances are invasive and thought to be due to microenvironment, but exact causes are unknown because of so many possible patched mutations Numbers vary, but about 70% of BCC have patched mutation

BCC’s can be caused by any one of numerous frameshift, nonsense, or missense loss of function mutations in one of the 23 Patched exons Frameshift and nonsense mutations affect a number of domains in the gene product. Truncated proteins (that often lost their c-terminus) often lose their inhibitory function, thus leaving Smoothened constitutively active. In such mutations, Southern Blots have shown accumulation of mutated PTCH, showing failure of negative feedback. For example, in the noncanonical pathway, mutation of the cleavage site (D1392N) (when cleaved, pro-apoptotic domain is exposed) leads to continuous cell proliferation. A truncated protein has the same result. Aszterbaum et al. 1998

In Gorlin Sydrome, mutations in Patched are inherited that lead to a predisposition to BCC all over the body Deleted or mutated PTCH1 gene that are inherited in an autosomal dominant pattern Inheritance leads to a genetic predisposition to basal cell carcinomas all over the body. Skeletal disformations, cysts, Large number of variable mutations at different places in the gene product. Also plays a role in medullablastomas and developmental defects in brain and skeletal formation. LOH (most often caused by UV light) at 9q22 leads to BCC. .002%

Basal Cell Carcinomas are usually treated by surgical removal, with high survival rates as they rarely metastasize. Also radiation, or topical creams (which stimulate the proliferation of natural killer cells like B type lymphocytes) Some trials have used cyclopamine which directly binds Smoothened, but it provides too toxic an environment for cells. Vismodegib (Erivedge) is drug taken for metastatic bcc

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