title: Proteome-wide discovery of mislocated proteins in cancer.
abstract: Several studies have sought systematically to identify protein subcellular locations, but an even larger task is to map which of these proteins conditionally relocates in disease (the mislocalizome). Here, we report an integrative computational framework for mapping conditional location and mislocation of proteins on a proteome-wide scale, called a conditional location predictor (CoLP). Using CoLP, we mapped the locations of over 10,000 proteins in normal human brain and in glioma. The prediction showed 0.9 accuracy using 100 location tests of 20 randomly selected proteins. Of the 10,000 proteins, over 150 have a strong likelihood of mislocation under glioma, which is striking considering that few mislocation events have been identified in this disease previously. Using immunofluorescence and Western blotting in both primary cells and tissues, we successfully experimentally confirmed 15 mislocations. The most common type of mislocation occurs between the endoplasmic reticulum and the nucleus; for example, for RNF138, TLX3, and NFRKB. In particular, we found that the gene for the mislocating protein GFRA4 had a nonsynonymous point mutation in exon 2. Moreover, redirection of GFRA4 to its normal location, the plasma membrane, led to marked reductions in phospho-STAT3 and proliferation of glioma cells. This framework has the potential to track changes in protein location in many human diseases.
authors.affiliation: Department of Biomedical Informatics, Ajou University School of Medicine, Suwon 443-749, Korea. kiylee@ajou.ac.kr
authors.forename: KiYoung
authors.initials: K
authors.lastname: Lee
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Byun
authors.forename: Wonpyo
authors.initials: W
authors.lastname: Hong
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Chuang
authors.forename: Chan-Gi
authors.initials: CG
authors.lastname: Pack
authors.forename: Enkhjargal
authors.initials: E
authors.lastname: Bayarsaikhan
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Paek
authors.forename: Hyosil
authors.initials: H
authors.lastname: Kim
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.forename: Bonghee
authors.initials: B
authors.lastname: Lee
mesh_terms: D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D063990:Gene Ontology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D058977:Molecular Sequence Annotation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D021381:Protein Transport; D020543:Proteome / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D029961:Zebrafish Proteins
chemical_list: C491860:GFRA4 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C417670:KIF13A protein, human; D009419:Nerve Tissue Proteins; D020543:Proteome; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D029961:Zebrafish Proteins; C110758:persephin; C577594:RNF138 protein, human; D044767:Ubiquitin-Protein Ligases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D016547:Kinesins