Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.
Pubmed ID: 24209692 RIS Download
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Software for macromolecular model building, model completion and validation, and protein modelling using X-ray data. Coot displays maps and models and allows model manipulations such as idealization, rigid-body fitting, ligand search, Ramachandran plots, non-crystallographic symmetry and more. Source code is available.
View all literature mentionsCell line C2C12 is a Spontaneously immortalized cell line with a species of origin Mus musculus (Mouse)
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line COS-7 is a Transformed cell line with a species of origin Chlorocebus aethiops (Green monkey)
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsStrain Type: Not Specified This is a legacy resource.
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