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Cytokines Activate Src Kinase and Inhibit EGFR‐Mediated Repair Mechanisms via Mig6 in Pancreatic Beta Cells
Author(s) -
Fong Kimberley M.,
Rezaeizadeh Alireza,
Chen YiChun,
Fueger Patrick T.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.715.7
Subject(s) - microbiology and biotechnology , beta cell , epidermal growth factor receptor , proto oncogene tyrosine protein kinase src , tyrosine kinase , kinase , egfr inhibitors , signal transduction , cytokine , cancer research , chemistry , biology , receptor , immunology , insulin , endocrinology , islet , biochemistry
Type 1 diabetes (T1D) is caused by autoimmune‐mediated destruction of insulin‐producing beta cells. Following beta cell injury, the pancreas attempts to launch a cellular repair and regenerative program, yet it fails to completely restore functional beta cell mass. One component of the regenerative program is epidermal growth factor receptor (EGFR) signaling. Upon irreparable beta cell damage, EGFR signaling is dampened, disrupting attempts to restore functional beta cell mass and maintain normoglycemia. We previously demonstrated that the negative feedback inhibitor of EGFR, Mitogen‐inducible gene 6 (Mig6), is induced by the pro‐inflammatory cytokines central to the beta cell destruction in T1D. We also established that pro‐inflammatory cytokines suppress EGFR activation, and siRNA‐mediated suppression of Mig6 restores EGFR signaling. Recently, Mig6 was reported to be phosphorylated and activated by Src kinase. Interestingly, Src increases cell proliferation by activating receptor tyrosine kinases, such as EGFR, yet it is also implicated in the production of reactive oxygen species, including nitric oxide (NO). We hypothesized that pro‐inflammatory cytokines activate Src kinase, and that along with NO, disrupt EGFR repair mechanisms through the induction and activation of Mig6. To test this hypothesis, we treated 832/13 cells independently with cytokines and high glucose and identified that these conditions increase the activation of Src. We confirmed these results ex vivo in mouse islets. Additionally, NO induces Mig6, which attenuates EGFR signaling, and NO synthase inhibition blocks the cytokine‐mediated induction of Mig6, thereby restoring cytokine‐impaired EGFR signaling. Interestingly, Src knockout mice appear to have a higher beta cell mass, and mice lacking pancreatic Mig6 have preserved beta cell mass following treatment with streptozotocin, which also induces NO. Our work suggests that Src kinase may be involved in the progression to T1D by activating Mig6, and may be a component of a feedback mechanism that can be targeted to preserve beta cell mass in T1D.