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Cell Rep. 2017 Sep 19;20(12):2775-2783. doi: 10.1016/j.celrep.2017.08.025.

A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress.

Author information

1
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: shashi.kant@umassmed.edu.
2
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
6
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA. Electronic address: roger.davis@umassmed.edu.

Abstract

Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH2-terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV. These interactions are required for SRC-induced activation of VAV and the subsequent engagement of a JIP1-tethered JNK signaling module. The JIP1 scaffold protein, therefore, plays a dual role in FFA signaling by coordinating upstream SRC functions together with downstream effector signaling by the JNK pathway.

KEYWORDS:

JIP1; JNK; fatty acid; insulin resistance

PMID:
28930674
PMCID:
PMC5659285
DOI:
10.1016/j.celrep.2017.08.025
[Indexed for MEDLINE]
Free PMC Article

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