The role of MerTK in promoting cell migration is enhanced by the oncogenic Ras/IL-33 signaling axis

Satoshi Ohta, Kenji Tago, Takahiro Kuchimaru, Megumi Funakoshi-Tago, Hisanaga Horie, Chihiro Aoki-Ohmura, Jitsuhiro Matsugi, Ken Yanagisawa

Research output: Contribution to journalArticlepeer-review

Abstract

Ras genes are frequently mutated in many cancer types; however, there are currently no conclusively effective anticancer drugs against Ras-induced cancer. Therefore, the downstream effectors of Ras signaling need to be identified for the development of promising novel therapeutic approaches. We previously reported that oncogenic Ras induced the expression of NF-HEV/IL-33, a member of the interleukin-1 family, and showed that intracellular IL-33 was required for oncogenic Ras-induced cellular transformation. In the present study, we demonstrated that the c-Mer proto-oncogene tyrosine kinase (MerTK), a receptor tyrosine kinase, played essential roles in oncogenic Ras/IL-33 signaling. The expression of MerTK was enhanced in transformed NIH-3T3 cells by the expression of oncogenic Ras, H-Ras (G12V), in an IL-33-dependent manner. In human colorectal cancer tissues, MerTK expression also correlated with IL-33 expression. The knockdown of IL-33 or MerTK effectively attenuated the migration of NIH-3T3 cells transformed by H-Ras (G12V) and A549, LoVo, and HCT116 cells harboring an oncogenic K-Ras mutation. Furthermore, the suppression of Ras-induced cell migration by the knockdown of IL-33 was rescued by the enforced expression of MerTK. The present results also revealed that MerTK was effectively phosphorylated in NIH-3T3 cells transformed by Ras (G12V). Ras signaling was essential for the tyrosine phosphorylation of MerTK, and the kinase activity of MerTK was indispensable for accelerating cell migration. Collectively, the present results reveal a novel role for MerTK in cancer malignancy, which may be utilized to develop novel therapeutic strategies that target Ras-transformed cells.

Original languageEnglish
JournalFEBS Journal
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • cell migration
  • colorectal cancer
  • IL-33
  • MerTK
  • Ras

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'The role of MerTK in promoting cell migration is enhanced by the oncogenic Ras/IL-33 signaling axis'. Together they form a unique fingerprint.

Cite this