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

Publication date: 19 September 2017 Source:Cell Reports, Volume 20, Issue 12 Author(s): Shashi Kant, Claire L. Standen, Caroline Morel, Dae Young Jung, Jason K. Kim, Wojciech Swat, Richard A. Flavell, Roger J. Davis 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. Graphical abstract Teaser Kant et al. demonstrate that scaffold protein JIP1 is required for palmitate-stimulated redistribution of SRC to lipid rafts. Phosphorylation of JIP1 on tyrosine mediates SH2 domain interactions with both SRC and the RAC exchange factor VAV. This signaling complex causes RAC-dependent activation of...
Source: Cell Reports - Category: Cytology Source Type: research