title: Proteolysis of EphA2 Converts It from a Tumor Suppressor to an Oncoprotein.
abstract: Eph receptor tyrosine kinases are considered candidate therapeutic targets in cancer, but they can exert opposing effects on cell growth. In the presence of its ligands, Eph receptor EphA2 suppresses signaling by other growth factor receptors, including ErbB, whereas ligand-independent activation of EphA2 augments ErbB signaling. To deploy EphA2-targeting drugs effectively in tumors, the anti-oncogenic ligand-dependent activation state of EphA2 must be discriminated from its oncogenic ligand-independent state. Because the molecular basis for the latter is little understood, we investigated how the activation state of EphA2 can be switched in tumor tissue. We found that ligand-binding domain of EphA2 is cleaved frequently by the membrane metalloproteinase MT1-MMP, a powerful modulator of the pericellular environment in tumor cells. EphA2 immunostaining revealed a significant loss of the N-terminal portion of EphA2 in areas of tumor tissue that expressed MT1-MMP. Moreover, EphA2 phosphorylation patterns that signify ligand-independent activation were observed specifically in these areas of tumor tissue. Mechanistic experiments revealed that processing of EphA2 by MT1-MMP promoted ErbB signaling, anchorage-independent growth, and cell migration. Conversely, expression of a proteolysis-resistant mutant of EphA2 prevented tumorigenesis and metastasis of human tumor xenografts in mice. Overall, our results showed how the proteolytic state of EphA2 in tumors determines its effector function and influences its status as a candidate biomarker for targeted therapy.
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Koshikawa
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hoshino
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Minegishi
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Tomari
authors.affiliation: Department of Obstetrics, Fukuoka University, Fukuoka, Japan.
authors.forename: Sung-Ouk
authors.initials: SO
authors.lastname: Nam
authors.affiliation: Department of Pathology, Fukuoka University, Fukuoka, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Department of Otorhinolaryngology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sueta
authors.affiliation: Department of Otorhinolaryngology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Obstetrics, Fukuoka University, Fukuoka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Pathology, Fukuoka University, Fukuoka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nabeshima
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan. Integrated Center for Advanced Medical Technologies, Kochi Medical School, Kochi, Japan. mseiki@ims.u-tokyo.ac.jp.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis; D034622:RNA Interference; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D025521:Tumor Suppressor Proteins; D036104:Receptor, EphA2; D053511:Matrix Metalloproteinase 14