The gene fusion KIAA1549::BRAF is a common oncogenic driver in pediatric pilocytic astrocytoma. The chimeric fusion protein that comprises most of the type 1 transmembrane KIAA1549 protein fused in its C-terminal cytosolic domain to the truncated BRAF oncogene without its N-terminal autoinhibitory domains. KIAA1549 has a large N-terminal ectodomain that undergoes extensive O-mannosylation directed by the POMT1/2 protein O-mannosyltransferase complex localized in the ER. Here, we investigated how posttranslational modifications contribute to KIAA1549 protein maturation in the secretory pathway. Using a panel of KIAA1549 expression constructs and glycoengineered HEK293 cells, we provide evidence that O-mannosylation of the KIAA1549 ectodomain is required for ER exit, acquisition of complex N-glycans, and subsequent furin-like cleavage in the Golgi. In the absence of POMT1/2 O-mannosylation KIAA1549 is retained in ER and fails to undergo proprotein processing. Our findings confirm and extend our previous studies with the KIAA1549::BRAF fusion protein, where oncogenic transformation was dependent on POMT1/2 O-mannosylation and affected on furin processing. Thus, these intrinsic posttranslational modifications of the KIAA1549 ectodomain are critical determinants of the cellular trafficking that lead to activation of the BRAF oncogene, potentially involving a cascade of cleavage events in the Golgi that ultimately release a truncated but fully active BRAF kinase domain into the cytosol.
Gloria Kyrila, Serpil Ahmed, Anna Borgenvik et al.· Journal of Biological Chemis...· 0 citations
The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.
Dina Elharouni, Mushriq Al-Jazrawe, Seongmin Choi et al.· Nature· 2 citations
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