Fyn activation of mTORC1 stimulates the IRE1 α-JNK pathway, leading to cell death

Yichen Wang, Eijiro Yamada, Haihong Zong, Jeffrey E. Pessin

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Wepreviously 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 mTORC1with 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.

Original languageEnglish (US)
Pages (from-to)24772-24783
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number41
DOIs
StatePublished - Oct 9 2015

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MAP Kinase Signaling System
Cell death
Endoplasmic Reticulum Stress
Cell Death
Chemical activation
Skeletal Muscle
Thapsigargin
Muscle
Sirolimus
Muscles
Transgenic Mice
Cell Culture Techniques
Phosphorylation
Phenotype
mechanistic target of rapamycin complex 1
Fibers

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Fyn activation of mTORC1 stimulates the IRE1 α-JNK pathway, leading to cell death. / Wang, Yichen; Yamada, Eijiro; Zong, Haihong; Pessin, Jeffrey E.

In: Journal of Biological Chemistry, Vol. 290, No. 41, 09.10.2015, p. 24772-24783.

Research output: Contribution to journalArticle

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