Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation
Keywords
mut-drivers, targeted therapy, clinical cancer data, posttranslational modification proteomics databases
Abstract
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 posttranslational 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 nonreceptor tyrosine kinases (NRTK) 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.
BYU ScholarsArchive Citation
Balasooriya, Eranga R.; Madhusanka, Deshan; López-Palacios, Tania P.; Eastmond, Riley J.; Jayatunge, Dasun; Owen, Jake J.; Gashler, Jack S.; Egbert, Christina M.; Bulathsinghalage, Chanaka; Liu, Lu; Piccolo, Stephen R.; and Andersen, Joshua L., "Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation" (2023). Faculty Publications. 7351.
https://scholarsarchive.byu.edu/facpub/7351
Document Type
Peer-Reviewed Article
Publication Date
2023-10
Publisher
American Association for Cancer Research
Language
English
College
Life Sciences
Department
Biology
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