title: Fyn Activation of mTORC1 Stimulates the IRE1α-JNK Pathway, Leading to Cell Death.
abstract: We previously reported that the skeletal muscle-specific overexpression of Fyn in mice resulted in a severe muscle wasting phenotype despite the activation of mTORC1 signaling. To investigate the bases for the loss of muscle fiber mass, we examined the relationship between Fyn activation of mTORC1, JNK, and endoplasmic reticulum stress. Overexpression of Fyn in skeletal muscle in vivo and in HEK293T cells in culture resulted in the activation of IRE1α and JNK, leading to increased cell death. Fyn synergized with the general endoplasmic reticulum stress inducer thapsigargin, resulting in the activation of IRE1α and further accelerated cell death. Moreover, inhibition of mTORC1 with rapamycin suppressed IRE1α activation and JNK phosphorylation, resulting in protecting cells against Fyn- and thapsigargin-induced cell death. Moreover, rapamycin treatment in vivo reduced the skeletal muscle IRE1α activation in the Fyn-overexpressing transgenic mice. Together, these data demonstrate the presence of a Fyn-induced endoplasmic reticulum stress that occurred, at least in part, through the activation of mTORC1, as well as subsequent activation of the IRE1α-JNK pathway driving cell death.
authors: From the Departments of Molecular Pharmacology and.
authors: Yichen
authors: Y
authors: Wang
authors: the Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
authors: Eijiro
authors: E
authors: Yamada
authors: Medicine, Albert Einstein College of Medicine, Bronx, New York 10461 and.
authors: Haihong
authors: H
authors: Zong
authors: From the Departments of Molecular Pharmacology and Medicine, Albert Einstein College of Medicine, Bronx, New York 10461 and Jeffrey.pessin@einstein.yu.edu.
authors: Jeffrey E
authors: JE
authors: Pessin
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D046912:Multiprotein Complexes; D019284:Thapsigargin; D051076:Proto-Oncogene Proteins c-fyn; C528229:ERN1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases
keywords: Fyn; IRE1α; c-Jun N-terminal kinase (JNK); cell death; endoplasmic reticulum stress (ER stress); mammalian target of rapamycin (mTOR); skeletal muscle