Proteolysis of EphA2 converts it from a tumor suppressor to an oncoprotein

Naohiko Koshikawa, Daisuke Hoshino, Hiroaki Taniguchi, Tomoko Minegishi, Taizo Tomari, Sung Ouk Nam, Mikiko Aoki, Takayuki Sueta, Takashi Nakagawa, Shingo Miyamoto, Kazuki Nabeshima, Alissa M. Weaver, Motoharu Seiki

研究成果: Contribution to journalArticle査読

25 被引用数 (Scopus)

抄録

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 Erb B, 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.

本文言語英語
ページ(範囲)3327-3339
ページ数13
ジャーナルCancer Research
75
16
DOI
出版ステータス出版済み - 8 15 2015
外部発表はい

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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