Disease relevance of ptc

• This regulatory pathway appears to function also in vertebrates, where defects in ptc cause basal cell carcinoma, tumors of epidermal stem cell origin [1].
• We identified a mutation in patched (ptc), an inhibitor of Hh signalling, in a genetic screen for regulators of the Retinoblastoma (Rb) pathway in Drosophila [2].
• This suggests a role for ptc in the response to ionizing radiation and provides a model for both the systemic (developmental) and stochastic (cancer) abnormalities observed in Gorlin syndrome [3].
• Here we report that mice heterozygous for ptc develop many of the features characteristic of Gorlin syndrome and that they exhibit a high incidence of rhabdomyosarcomas (RMS), the most common soft-tissue sarcoma in children [3].
• Recently, a subset of medulloblastoma, the most common malignant brain tumor in children, was found to contain somatic mutations in the human ptc gene [4].

High impact information on ptc

• Here we present evidence that Patched destabilizes Smoothened in the absence of Hedgehog [5].
• Their range of action is limited by a C-terminal cholesterol tether and the upregulation of Patched (Ptc) receptor levels [6].
• Analysis of the mutant phenotype demonstrates that both segment and parasegment borders are included in the duplicated pattern of ptc mutants [7].
• The pattern of expression does not directly predict the transformation seen in ptc mutant embryos, suggesting that ptc participates in cell interactions that establish pattern within the segment [7].
• The syndrome results from germline mutations of the human homolog of the drosophila segment polarity gene patched (ptc) [3].

Biological context of ptc

• A point mutation in the motor domain of Cos2 results in a dominant-negative form of the protein that derepresses dpp but not ptc [8].
• A single pulse of Patched transgene expression has little or no effect on the segmental pattern, as has been previously reported [9].
• Finally, we identify sequences in the promoter region of the ptc gene, a primary target of Hh signaling, that are identical to the consensus-binding sequence of the GLI protein and are required for reporter gene expression in response to Hh activity [10].
• Attenuation of Hh signalling activity caused by loss of fused function results in a striking down-regulation of col, ptc, and engrailed (en) symmetrically about the DV boundary [11].
• Furthermore, ptcIN is a dominant suppressor of the oro embryonic lethal phenotype, suggesting a close and dose-dependent relationship between oro and ptc in Hh signal transduction. oro function is also required in imaginal development [12].

Anatomical context of ptc

• G509V exhibits vesicular localisation identical to the wild-type protein, but the C-terminal truncated Patched molecule is localised predominantly to the plasma membrane [13].
• Sonic Hedgehog (Shh) and Patched (Ptc) were found only in the dorsal tongue epithelium [14].
• Mutant analysis shows that the lack of ptc activity alters the fate of optic-lobe primordia precursors [15].
• Sonic hedgehog is also involved in the induction of ventral cell type in the developing somites. ptc is a key gene in the Drosophila hedgehog signaling pathway where it is involved in transducing the hedgehog signal and is also a transcriptional target of the signal [16].
• We report that 14% of ptc+/- mice develop central nervous system tumors in the posterior fossa by 10 months of age, with peak tumor incidence occurring between 16 and 24 weeks of age [4].

Associations of ptc with chemical compounds

• Here we present evidence that removing activity of the gene encoding cyclic AMP-dependent protein kinase A (pka) is functionally equivalent to removing ptc activity or to providing cells with the Hh signal [17].
• Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation [18].

Physical interactions of ptc

• In vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex [19].
• Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein [20].

Regulatory relationships of ptc

• High levels of Patched expression might therefore overcome the repression and repress wg in all cells [9].
• Similarly, patched (ptc) is also ectopically expressed in such posterior compartment en-inv- null clones [21].
• Hence, mutations within the ptc gene that result in the failure of Ptc to inhibit Smo lead to constitutive activity of the Hh signalling pathway and to cancer, such as basal cell carcinoma [22].
• The ectopic expression of hh that is normally induced in patched (ptc) mutant embryos does not appear in ptc en double mutants [23].
• We propose that ptc controls dpp expression in the imaginal discs, and that the restricted expression of dpp near the anterior-posterior compartment boundary is essential to maintain the wild-type morphology of the wing disc [24].

Other interactions of ptc

• Expression of this reporter construct expands in ptc mutants and responds to hh activity [25].
• Activity of this element depends on ptc, but it contains no consensus Ci-binding sites [25].
• patched overexpression causes loss of wingless expression in Drosophila embryos [9].
• Repression of ptc in the presence of the dominant-negative form of Cos2 requires Su(fu), which is phosphorylated in response to Hh in vivo [8].
• We show that, at the A/P boundary, Fu kinase activity is involved in the maintenance of high ptc expression and in the induction of late anterior engrailed (en) expression [26].

Analytical, diagnostic and therapeutic context of ptc

• Immunocytochemistry data and fractionation studies also show that Patched seems to be required for transport of Smoothened to the membrane [27].
• Immunoprecipitation studies show that Patched specifically interacts with caveolin-1, whereas Smoothened does not [27].

References