The TAM Family: Phosphatidylserine Sensing Receptor Tyrosine Kinases Gone Awry in Cancer

Nat Rev Cancer. 2014 Dec;14(12):769-85. doi: 10.1038/nrc3847.

Abstract

The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Resistance, Neoplasm
  • Humans
  • Immunity, Innate
  • Neoplasm Metastasis
  • Neoplasms / enzymology*
  • Neovascularization, Pathologic / etiology
  • Phosphatidylserines / metabolism
  • Platelet Aggregation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Signal Transduction
  • c-Mer Tyrosine Kinase

Substances

  • Phosphatidylserines
  • Proto-Oncogene Proteins
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase