TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL

Mol Cell. 2019 Aug 8;75(3):457-468.e4. doi: 10.1016/j.molcel.2019.05.022. Epub 2019 Jun 20.

Abstract

Necroptosis, a cell death pathway mediated by the RIPK1-RIPK3-MLKL signaling cascade downstream of tumor necrosis factor α (TNF-α), has been implicated in many inflammatory diseases. Members of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases are known for their anti-apoptotic, oncogenic, and anti-inflammatory roles. Here, we identify an unexpected role of TAM kinases as promoters of necroptosis, a pro-inflammatory necrotic cell death. Pharmacologic or genetic targeting of TAM kinases results in a potent inhibition of necroptotic death in various cellular models. We identify phosphorylation of MLKL Tyr376 as a direct point of input from TAM kinases into the necroptosis signaling. The oligomerization of MLKL, but not its membranal translocation or phosphorylation by RIPK3, is controlled by TAM kinases. Importantly, both knockout and inhibition of TAM kinases protect mice from systemic inflammatory response syndrome. In conclusion, this study discovers that immunosuppressant TAM kinases are promoters of pro-inflammatory necroptosis, shedding light on the biological complexity of the regulation of inflammation.

Keywords: Axl; MLKL; Mer; TAM kinases; Tyro3; cell death; necroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Necroptosis / genetics
  • Phosphorylation
  • Protein Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Systemic Inflammatory Response Syndrome / genetics*
  • Systemic Inflammatory Response Syndrome / pathology
  • Tumor Necrosis Factor-alpha / genetics
  • c-Mer Tyrosine Kinase / genetics*

Substances

  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha
  • MLKL protein, human
  • Protein Kinases
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • TYRO3 protein, human
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases