Editors' ChoiceCell death

TAMs target MLKL

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Science Signaling  25 Jun 2019:
Vol. 12, Issue 587, eaay4753
DOI: 10.1126/scisignal.aay4753

TAM family kinases promote necroptosis by stimulating the phosphorylation and oligomerization of the pseudokinase MLKL.

Necroptosis is a necrotic form of cell death that depends on signaling downstream of the tumor necrosis factor receptor (TNFR) and other death receptors. In response to TNF-α, the receptor-interacting protein kinase 1(RIPK1) associates with and activates RIPK3 in a complex called the necrosome. Activated RIPK3 phosphorylates and activates the pseudokinase mixed lineage kinase domain–like (MLKL), which translocates to the plasma membrane, oligomerizes, and forms pores that cause cell lysis. Najafov et al. found that the loss of Tyro3, a member of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases, inhibited necroptosis of cell lines and primary fibroblasts induced by a cocktail of drugs including TNF-α (TSZ). TAM kinases are considered to be anti-apoptotic and mediate the resolution of inflammation. Loss or inhibition of TAM kinases had no effect on TSZ-induced RIPK activation, necrosome formation, or MLKL phosphorylation and translocation; however, MLKL oligomerization was inhibited. During necroptosis, Tyro3 physically interacted with MLKL and induced phosphorylation of Tyr376. In cells expressing a constitutively active mutant MLKL that spontaneously oligomerizes, inhibition or loss of Tyro3 prevented necroptosis. In MLKL-deficient cells, expression of wild-type MLKL, but not the Y376A mutant MLKL, rendered the cells sensitive to TSZ-induced necroptosis. Treatment of mice with TNF-α and the caspase inhibitor zVAD.fmk (TZ) induces systemic inflammatory response syndrome (SIRS), in which necroptosis plays a major role. However, mice triply deficient in Tyro3, Axl, and MerTK were protected from TZ-induced SIRS and exhibited substantially less tyrosine-phosphorylation of MLKL in the liver than did TZ-treated wild-type mice. Treatment of wild-type mice with a TAM kinase inhibitor increased their survival after exposure to TZ and also inhibited TZ-induced MLKL tyrosine-phosphorylation. Together, these data suggest that TAM family members promote necroptosis by phosphorylating MLKL and inducing its oligomerization. Given that TAM kinases are frequently amplified in cancers, these data suggest that some cancer cells may be sensitized to necroptosis.

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