Fellowship/Allen-Klee: Regulation of insulin signaling by Rlf

  • Post, Steven (PI)

Grants and Contracts Details

Description

Insulin is beneficial for cardiac cell survival and function. For example, impaired insulin action contributes to pathological conditions such as diabetic cardiomyopathy. Conversely, increased insulin signaling is thought to protect cardiomyocytes from ischemic injury when administered as part of Glucose-Insulin-Potassium (GIK) infusion therapy. Although insulin plays a fundamental role in cardioprotection and cardiac maintenance, the mechanism by which insulin promotes these effects is not well understood. Insulin binding to its receptor promotes the activation of the insulin receptor substrate (IRS) via insulin receptor-mediated phosphorylation of tyrosine residues on IRS. Activation of IRS mediates activation of intracellular signaling cascades, in part, by activating the small GTPase, Ras. Ras interacts with multiple effectors to stimulate both cardioprotective (e.g. PI3-kinase-Akt and Raf-MEK-ERK) and apoptotic (e.g. MEKK1-JNK) cascades. Identifying the factors that modulate these kinase cascades is therefore, of fundamental importance to understanding cardiac pathophysiology. We have identified the RaIGEF-like factor (Rlf) as a protein that interacts with Ras in the heart. My preliminary results obtained in neonatal rat ventricular myocytes (NRVMs) indicate that Rlf overexpresion enhances insulin-induced IRS phosphorylation and PI3-kinase-Akt activation while inhibiting insulin-induced JNK activation. Whether IRS is specifically involved in Rlf-mediated upregulation of Pl3-kinase activation and the role of Rlf-mediated Ral activation is not known and will be investigated in this proposal. My hypothesis is that Rlf enhances insulin-induced Pl3-kinase activation through Ral mediated inhibition of JNK and enhanced IRS activation. The aims for this proposal are: Specific Aim 1: To determine the role of JNK and IRS in Rlf-mediated upregulation of insulin-induced Pl3-kinase activation and; Specific Aim 2: To determine the role of Ral in JNK inhibition and enhancement of IRS and Pl3-kinase activation.
StatusFinished
Effective start/end date7/1/066/30/08

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