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Phosphorylation of selected serines in the PTB domain of IRS‐2 inhibits its function and promotes insulin resistance under pathological conditions
Author(s) -
Gurevitch Diana,
BuraHalfon Sigalit,
Ronen Denise,
Zick Yehiel
Publication year - 2007
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.21.5.a293-c
Subject(s) - insulin receptor , phosphorylation , insulin resistance , insulin receptor substrate , irs1 , insulin , microbiology and biotechnology , signal transduction , kinase , biology , medicine , chemistry , endocrinology
Ser/Thr phosphorylation of Insulin receptor substrate (IRS) proteins negatively modulates insulin signaling both under physiological and insulin resistance states. Ser phosphorylation of IRS proteins leads to their dissociation from the insulin receptor (IR) thus terminating insulin signaling. We mutated into Ala five potential Ser inhibitory sites located proximal to the PTB domain of IRS‐2, which mediates IRS‐2 interactions with the juxtamembrane domain of IR. When overexpressed in CHO‐T, the mutated IRS‐2 5A , unlike IRS‐2 WT , maintained its Tyr‐phosphorylated active conformation following prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance such as sphingomyelinase, prior to acute insulin treatment. The observed protective effect of IRS‐2 5A was not limited to IRS‐2 phosphorylation, but was further propagated to downstream effectors of IRS‐2. When overexpressed in Min 6 (beta cell line), IRS‐2 5A better protected the cells from apoptosis induced by a combination of IL‐1β, INF‐γ, TNF‐α and Fas ligand, when compared to cells overexpressing IRS‐2 WT . This work suggests that phosphorylation of Ser sites surrounding the PTB domain of IRS‐2 by insulin‐stimulated IRS kinases, or by IRS kinases triggered by inducers of insulin resistance, inhibits insulin signal transduction. Moreover, mutation of these Ser sites increases the functionality of IRS‐2 and therefore protects beta cells from apoptosis triggered by pro‐inflammatory cytokines