PTPRD, a well‐established tumor suppressor gene, encodes the protein tyrosine phosphatase‐type D. This protein consists of three immunoglobulin‐like (Ig) domains, four to eight fibronectin type 3 ...(FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer‐associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer‐associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan‐binding pocket enhanced PTPRD's binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG‐mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.
Receptor protein tyrosine phosphatase‐type D (PTPRD) is a well‐established tumor suppressor gene product. A systematic analysis of 92 cancer‐associated point mutations within the extracellular domain (ECD) revealed that 69.6% (64 out of 92) of them suppressed total protein expression and/or plasma membrane localization. Furthermore, some mutations within the Ig domains adjacent to the glycosaminoglycan‐binding pocket enhanced the interaction between PTPRD and heparan sulfate proteoglycans (HSPGs) suggesting HSPG‐mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape ...of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
Terbinafine is one of the allylamine antifungal agents whose target is squalene epoxidase (SQLE). This agent has been extensively used in the therapy of dermatophyte infections. The incidence of ...patients with tinea pedis or unguium tolerant to terbinafine treatment prompted us to screen the terbinafine resistance of all
clinical isolates from the laboratory of the Centre Hospitalier Universitaire Vaudois collected over a 3-year period and to identify their mechanism of resistance. Among 2,056 tested isolates, 17 (≈1%) showed reduced terbinafine susceptibility, and all of these were found to harbor
gene alleles with different single point mutations, leading to single amino acid substitutions at one of four positions (Leu
, Phe
, Phe
, and His
) of the SQLE protein. Point mutations leading to the corresponding amino acid substitutions were introduced into the endogenous
gene of a terbinafine-sensitive
(formerly
) strain. All of the generated
transformants expressing mutated SQLE proteins exhibited obvious terbinafine-resistant phenotypes compared to the phenotypes of the parent strain and of transformants expressing wild-type SQLE proteins. Nearly identical phenotypes were also observed in
transformants expressing mutant forms of
SQLE proteins. Considering that the genome size of dermatophytes is about 22 Mb, the frequency of terbinafine-resistant clinical isolates was strikingly high. Increased exposure to antifungal drugs could favor the generation of resistant strains.
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