Spatially interacting phosphorylation sites and mutations in cancer

Huang, Kuan Lin; Scott, Adam; Zhou, Daniel Cui; Wang, Liang-Bo; Weerasinghe, Amila; Elmas, Abdulkadir; Liu, Ruiyang; Wu, Yige; Wendl, Michael C.; Wyczalkowski, Matthew A.; Baral, Jessika; Sengupta, Sohini; Lai, Chin‐Wen; Ruggles, Kelly V.; Payne, Samuel H.; Raphael, Benjamin J.; Fenyö, David; Chen, Ken; Mills, Gordon B.; Li, Ding

doi:10.1038/s41467-021-22481-w

Cited by 13 publications

(10 citation statements)

References 43 publications

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“…Notably, TP53 missenses are associated with higher protein expression in multiple cancer cohorts, in addition to the expected reduction in expression associated with truncations ( Figure 5A ). Such cis-effect of functional TP53 missense mutations had previously been observed through immunohistochemistry (IHC 24 ) or MS global proteomics experiments 25 . Here, we hypothesized that functional TP53 missense mutations are more likely to show high levels of concurrent protein-level expression in the mutated tumor sample.…”

Section: Resultsmentioning

confidence: 68%

Mutation Impact on mRNA Versus Protein Expression across Human Cancers

Liu,

Elmas,

Huang

2023

Preprint

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Cancer mutations are often assumed to alter proteins, thus promoting tumorigenesis. However, how mutations affect protein expression has rarely been systematically investigated. We conduct a comprehensive analysis of mutation impacts on mRNA- and protein-level expressions of 953 cancer cases with paired genomics and global proteomic profiling across six cancer types. Protein-level impacts are validated for 47.2% of the somatic expression quantitative trait loci (seQTLs), including mutations from likely “long-tail” driver genes. Devising a statistical pipeline for identifying somatic protein-specific QTLs (spsQTLs), we reveal several gene mutations, includingNF1andMAP2K4truncations andTP53missenses showing disproportional influence on protein abundance not readily explained by transcriptomics. Cross-validating with data from massively parallel assays of variant effects (MAVE),TP53missenses associated with high tumor TP53 proteins were experimentally confirmed as functional. Our study demonstrates the importance of considering protein-level expression to validate mutation impacts and identify functional genes and mutations.

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Section: Resultsmentioning

confidence: 68%

Mutation Impact on mRNA Versus Protein Expression across Human Cancers

Liu,

Elmas,

Huang

2023

Preprint

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“…Further GSEA analysis showed that in high ZBTB9 expression samples, the G2M checkpoint, epithelial-mesenchymal transition, E2F targets, and KRAS-related signaling pathways were significantly activated, which has been reported to participate in tumor proliferation and progression [36,37]. In addition, the investigation of the correlation between ZBTB9 and KRAS signaling pathway demonstrated that ZBTB9 was evidently associated with MAPK1, NRAS, SHP2, SOS1, and KRAS2 (all play imperative roles in KRAS pathway [38][39][40]), suggesting that the malignant biological behaviors under ZBTB9 upregulation were probably mediating through this pathways. Blocking of ZBTB9 could have the potential value to optimize the efficacy of inhibitors against KRAS signaling pathways [41,42].…”

Section: Discussionmentioning

confidence: 95%

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Zhang

et al. 2022

J Transl Med

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Background Zinc finger and bric-a-brac/tramtrack/broad (ZBTB) domain-containing proteins have been reported to be associated with many tumors’ development. However, in tumor initiation and progression, the role of ZBTB9, one of the protein family, and its prognostic value were yet to be elucidated in Liver Hepatocellular Carcinoma (LIHC). Methods We used R software and online bioinformatics analysis tools such as GEPIA2, cBioPortal, TIMER2, Metascape, UALCAN, STRING, TISIDB, and COSMIC to investigate ZBTB9’s characteristics and function in LIHC, including abnormal expression, carcinogenic role, related signaling pathways and prognostic value. Furthermore, cell experiments (such as formation, wound healing, and transwell assays) and analyses based on clinical samples (such as immunohistochemistry (IHC) and promoter methylation analysis) were conducted to verify pivotal conclusions. Results ZBTB9 was overexpressed in LIHC samples compared to adjacent normal tissues. Through the analysis of genomic alteration and promoter hypomethylation, the clinical value and etiology of abnormal expression of ZBTB9 were preliminarily exlpored. Subsequent evidence showed that it could result in tumor progression and poor prognosis via activating cell cycle, DNA repair, MYC, and KRAS-associated signaling pathways as well as rendering immune dysregulation. After the knockdown of ZBTB9, evidently inhibited capacities of tumor cells proliferation and migration were observed. These results together indicated that ZBTB9 could be a promising prognostic biomarker and had the potential value to offer novel therapeutic targets for LIHC treatment. Conclusions ZBTB9 was identified as a novel biomarker to predict the prognosis and tumor progression in LIHC, and a promising therapeutic target to invert tumor development.

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“…This PTM database includes 485,308 nonredundant PTM sites and a variety of PTM types, including phosphorylation, ubiquitination, acetylation, glycosylation, and others, which expands upon previous approaches with limited PTM data sets or narrow PTM focus (refs. 61, 62 ; Supplementary Fig. S2A and S2B).…”

Section: Resultsmentioning

confidence: 99%

Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation

Balasooriya,

Madhusanka,

López-Palacios

et al. 2023

Molecular Cancer Research

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Beyond the most common oncogenes activated by mutation (mut-drivers) there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and post-translational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function. The list of putative mut-drivers includes established drivers and others with poorly understood roles in cancer. This ML model is available as a web application. As a case study, we focused the approach on non-receptor tyrosine kinases (NRTKs) and found a recurrent mutation in activated CDC42 kinase-1 (ACK1) that disrupts the Mig6 homology region (MHR) and ubiquitin-association (UBA) domains on the ACK1 C-terminus. By studying these domains in cultured cells, we found that disruption of the MHR domain helps activate the kinase while disruption of the UBA increases kinase stability by blocking its lysosomal degradation. This ACK1 mutation is analogous to lymphoma-associated mutations in its sister kinase, TNK1, which also disrupt a C-terminal inhibitory motif and UBA domain. This study establishes a mut-driver discovery tool for the research community and identifies a mechanism of ACK1 hyperactivation shared among ACK family kinases. Implications: This research identifies a potentially targetable activating mutation in ACK1 and other possible oncogenic mutations, including PTM-disrupting mutations, for further study.

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Spatially interacting phosphorylation sites and mutations in cancer

Cited by 13 publications

References 43 publications

Mutation Impact on mRNA Versus Protein Expression across Human Cancers

Mutation Impact on mRNA Versus Protein Expression across Human Cancers

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation

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