Somatic mutations in the cancer associated GPCR-like protein smoothened

2524 Recently, Hedgehog (Hh) signalling has been assigned roles in driving tumourigenesis and cancer development in several tissues. On the target cell of Hh signaling, in the absence of the Hh ligand, the membrane protein Patched (Ptch) represses the activity of the G protein-coupled receptor (GPCR)-like protein Smoothened (Smo). Upon Hh ligand binding to the receptor Ptch the repression of Smo is discontinued and signaling is initiated resulting in activation of the Gli transcription factors.
 Uncontrolled activation of the Hh pathway has been reported to result in distinct cancers of the skin (basal cell carcinoma, BCC), brain (medulloblastoma) and muscle (rhabdomyosarcoma). Mutations in Smo occur in approximately 10-20% of sporadic BCCs. These mutations may be so called gain-of-function mutations resulting in constitutively active proteins and subsequent activation of the Hh pathway. Mutations in Smo have also been reported to occur in medulloblastoma. However, the function and role of these mutations have not been closely addressed.
 In the Smo gene, to date 15 different mutations have been reported to occur in various types of cancers. We used gene reporter and differentiation assays to address the effect on Smo mediated signaling of the identified somatic mutations. The transformation potential of each mutant was addressed in dedicated assays. We have identified at least one mutation resulting in increased Smo signaling in the absence of the Hh ligand in addition to the previously known W535L Smo mutation. These mutations are located in an area of the seven transmembrane spanning protein Smo resembling the location in GPCR known to result in constitutively active receptors. Therefore, in addition to the previously known Smo mutation resulting in BCC further mutations in Smo have to be considered relevant for the development and maintenance of various cancers. Understanding the signaling properties of these constitutively active GPCR-like proteins may endorse the identification of novel targets for anticancer treatment.