Three Mitogen-Activated Protein Kinases Inhibit Insulin Signaling by Different Mechanisms in 3T3-L1 Adipocytes

Abstract

TNFalpha, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. To better understand the respective roles of these three MAPK pathways in insulin signaling and their contribution to insulin resistance, constitutively active MAPK/ERK kinase (MEK)1, MAPK kinase (MKK6), and MKK7 mutants were overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated transfection procedure. The MEK1 mutant, which activates ERK, markedly down-regulated expression of the insulin receptor (IR) and its major substrates, IRS-1 and IRS-2, mRNA and protein, and in turn reduced tyrosine phosphorylation of IR as well as IRS-1 and IRS-2 and their associated phosphatidyl inositol 3-kinase (PI3K) activity. The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI3K activity without exerting a significant effect on the IR. Finally, the MKK7 mutant, which activates JNK, reduced tyrosine phosphorylation of IRS-1 and IRS-2 and IRS-associated PI3K activity without affecting expression of the IR, IRS-1, or IRS-2. In the context of our earlier report showing down-regulation of glucose transporter 4 by MEK1-ERK and MKK6/3-p38, the present findings suggest that chronic activation of ERK, p38, or JNK can induce insulin resistance by affecting glucose transporter expression and insulin signaling, though via distinctly different mechanisms. The contribution of ERK is, however, the strongest.

FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

“…IRS-1 is the counterpart of FRS2 in the insulin signaling pathway and exhibits balanced PY and PT. Upon PS/T, either IRS-1 becomes a poor substrate for insulin receptor kinase [33] or its association with subcellular compartments and/or stability is probably altered [34,35]. FRS2 may also undergo similar changes.…”

Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance

“…Elevated levels of free fatty acids and cytokines, such as TNF-␣, IL-6, or IL-1 ␤, are involved in this process by activating stress pathways that impede insulin signaling and lead to a decreased insulin response (1). Among these pathways, activation of the MAP kinases (ERK 1 and 2) (2) and SAP kinases (JNK and p38MAPK) are crucial in the insulin resistance (3)(4)(5). One target of the MAP and SAP kinases is insulin receptor substrate (IRS)-1, which is phosphorylated on serine residues (3).…”

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

“…Upon activation by ER stress through IRE1α [30] , JNK can directly phosphorylate IRS-1 at Ser307 leading to the reduction of insulin-induced IRS-1 tyrosine phosphorylation and a decrease in activity of the insulin pathway [31,32] . Given that ATF6 might protect the insulin pathway by attenuating JNK pathway activity, the related ATF6 protection on IR phosphorylation from excessive tunicamycin stimulation is not connected with the p38 pathway Besides the JNK pathway, the MKK3/6-p38 and MEK1/2-ERK pathways are also associated with several key proteins within the insulin receptor signaling pathway (eg, IR, IRS, and AKT) [33][34][35][36][37] . We thereby hypothesized that the ERK or p38 pathways might be involved in ATF6's protection on insulin signaling from excessive ER stress stimulation.…”

“…Our results indicate that the MEK1/2-ERK pathway is associated with the ATF6 protection mechanism. Before our investigation, several studies reported that MEK exerted negative effects on the insulin signaling pathway via down-regulation [33][34][35] . Several diabetes-inducing agents have also been demonstrated as causing insulin resistance in a MEK-dependent manner [35,20] .…”

“…The MAPK signaling pathways MKK4/7-SAPK/JNK, MKK3/6-p38, and MEK1/2-ERK have been reported to play key roles in insulin resistance induced by excessive ER stress [33][34][35][36][37][38] . Therefore, the phosphorylation of JNK, p38 and ERK were examined in ATF6 over-expressing cells.…”