The MERTK Signalling Pathway in Cancer

Abstract

MERTK is a receptor tyrosine kinase that is aberrantly expressed in a number of cancers and is a member of the TAM family of RTKs, along with TYRO3 and AXL. Recent studies have elucidated a role for MERTK in a variety of oncogenic processes including cancer cell growth, proliferation, migration, invasion, apoptosis, survival and transcriptional regulation. In addition, MERTK also functions to suppress anti‐tumour immunity. These functions are mediated by MERTK signalling through classical oncogenic pathways such as MAPK/ERK, PI3K/AKT and JAK/STAT. Transcription factors, such as NF‐κB, as well as a number of apoptotic proteins have also been identified as key downstream signalling molecules. Multiple therapies that specifically target MERTK are in development. Clinical application of translational agents targeting MERTK has the potential to enhance outcomes for patients with a variety of types of cancer.

Key Concepts

  • MERTK is a member of the TAM family (Tyro‐3, Axl and MerTK) of receptor tyrosine kinases.
  • MERTK is activated by ligand‐induced dimerisation and subsequent auto‐phosphorylation of the kinase domain.
  • MERTK regulates known oncogenic and pro‐survival signalling pathways, including MAPK/ERK, PI3K/AKT, JAK/STAT, NF‐κB and other transcription factors, and numerous apoptotic proteins.
  • The outcome of physiologic MERTK signalling depends on which ligand stimulates the receptor and the function of MERTK in that cell type.
  • MERTK is aberrantly expressed in many solid tumours and haematological malignancies.
  • MERTK plays roles in cancer cell survival, proliferation, migration, invasion, apoptosis and transcriptional regulation.
  • MERTK plays a role in immune modulation of cancer cells.
  • Specific inhibition of MERTK is a promising therapeutic strategy.

Keywords: MERTK; RTK; cancer; TAM family; GAS6; oncogene; MAPK; PI3K; apoptosis

Figure 1. MERTK structure.
Figure 2. MERTK signalling pathways.
Figure 3. MERTK therapeutic targeting.
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Further Reading

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Pierce AM and Keating AK (2014) TAM receptor tyrosine kinases: expression, disease, and oncogenesis in the central nervous system. Brain Research 1542: 206–220.

Verma A, Warner SL, Vankayalapati H, Bearss DJ and Sharma S (2011) Targeting Axl and Mer kinases in cancer. Molecular Cancer Therapeutics 10 (10): 1763–1773.

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Hill, Amanda A, Carrico, Jacqueline, DeRyckere, Deborah, and Graham, Douglas K(Apr 2015) The MERTK Signalling Pathway in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025726]