ChiPPI: A novel method for mapping chimeric protein-protein interactions uncovers selection principles of protein fusion events in cancer

Milana Frenkel-Morgenstern, Alessandro Gorohovski, Somnath Tagore, Vaishnovi Sekar, Miguel Vazquez, Alfonso Valencia

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Fusion proteins, comprising peptides deriving from the translation of two parental genes, are produced in cancer by chromosomal aberrations. The expressed fusion protein incorporates domains of both parental proteins. Using a methodology that treats discrete protein domains as binding sites for specific domains of interacting proteins, we have cataloged the protein interaction networks for 11 528 cancer fusions (ChiTaRS-3.1). Here, we present our novel method, chimeric protein-protein interactions (ChiPPI) that uses the domain-domain cooccurrence scores in order to identify preserved interactors of chimeric proteins. Mapping the influence of fusion proteins on cell metabolism and pathways reveals that ChiPPI networks often lose tumor suppressor proteins and gain oncoproteins. Furthermore, fusions often induce novel connections between non-interactors skewing interaction networks and signaling pathways. We compared fusion protein PPI networks in leukemia/lymphoma, sarcoma and solid tumors finding distinct enrichment patterns for each disease type. While certain pathways are enriched in all three diseases (Wnt, Notch and TGF β), there are distinct patterns for leukemia (EGFR signaling, DNA replication and CCKR signaling), for sarcoma (p53 pathway and CCKR signaling) and solid tumors (FGFR and EGFR signaling). Thus, the ChiPPI method represents a comprehensive tool for studying the anomaly of skewed cellular networks produced by fusion proteins in cancer.

Original languageEnglish
Pages (from-to)7094-7105
Number of pages12
JournalNucleic Acids Research
Volume45
Issue number12
DOIs
StatePublished - 7 Jul 2017

Bibliographical note

Publisher Copyright:
© The Author(s) 2017.

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