RT Journal Article SR Electronic T1 ETV2 regulates PARP-1 binding protein to induce ER stress–mediated death in tuberin-deficient cells JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201369 DO 10.26508/lsa.202201369 VO 5 IS 5 A1 Shikshya Shrestha A1 Anthony Lamattina A1 Gustavo Pacheco-Rodriguez A1 Julie Ng A1 Xiaoli Liu A1 Abhijeet Sonawane A1 Jewel Imani A1 Weiliang Qiu A1 Kosmas Kosmas A1 Pierce Louis A1 Anne Hentschel A1 Wendy K Steagall A1 Rieko Onishi A1 Helen Christou A1 Elizabeth P Henske A1 Kimberly Glass A1 Mark A Perrella A1 Joel Moss A1 Kelan Tantisira A1 Souheil El-Chemaly YR 2022 UL https://www.life-science-alliance.org/content/5/5/e202201369.abstract AB 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.