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Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes ( TSC1  or  TSC2 ) and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Here, we report that E26 transformation–specific (ETS) variant transcription factor 2 (ETV2) is a critical regulator of  Tsc2 -deficient cell survival. ETV2 nuclear localization in  Tsc2 -deficient cells is mTORC1-independent and is enhanced by spleen tyrosine kinase (Syk) inhibition. In the nucleus, ETV2 transcriptionally regulates poly(ADP-ribose) polymerase 1 binding protein (PARPBP) mRNA and protein expression, partially reversing the observed down-regulation of PARPBP expression induced by mTORC1 blockade during treatment with both Syk and mTORC1 inhibitors. In addition, silencing Etv2 or  Parpbp  in  Tsc2 -deficient cells induced ER stress and increased cell death in vitro and in vivo. We also found  ETV2  expression in human cells with loss of heterozygosity for  TSC2 , lending support to the translational relevance of our findings. In conclusion, we report a novel ETV2 signaling axis unique to Syk inhibition that promotes a cytocidal response in  Tsc2 -deficient cells and therefore maybe a potential alternative therapeutic target in LAM.

ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells