RESUMO
Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the ß-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.
Assuntos
Luxação do Quadril , Osteosclerose , Tanquirases , Humanos , Tanquirases/genética , Tanquirases/metabolismo , Proteína Axina/genética , Proteína Axina/metabolismo , Via de Sinalização Wnt/genética , Osteosclerose/genética , beta Catenina/metabolismoRESUMO
Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling. DecryptM profiling of 31 cancer drugs in 13 cell lines demonstrates the broad applicability of the approach. The resulting 1.8 million dose-response curves are provided as an interactive molecular resource in ProteomicsDB.
Assuntos
Antineoplásicos , Apoptose , Processamento de Proteína Pós-Traducional , Proteômica , Antígenos CD20/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteômica/métodos , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , HumanosRESUMO
Ranes et al. (2021) report on an in vitro reconstituted ß-catenin destruction complex and elucidate the contributions of full-length and cancer-related mutated core components to ß-catenin turnover, thereby advancing our understanding of the inner workings of this tumor suppressor complex.