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Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

The ageing suppressor -klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of -klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, -klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of -klotho is incompatible with its purported glycosidase activity. Thus, shed -klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling., Author(s): Gaozhi Chen [1, 2]; Yang Liu [2]; Regina Goetz [2]; Lili Fu [1, 2]; Seetharaman Jayaraman [3]; Ming-Chang Hu [4]; Orson W. Moe [4]; Guang Liang [1]; Xiaokun Li [...]

An analysis of several protein-tyrosine kinases suggests that the specificity of these kinases arises due to the ability of the SH2 domains to identify phosphotyrosine. The receptor tyrosine kinases phosphorylate group III SH2 domain-recognized peptides, while those recognized by group I SH2 domains are phosphorylated by cytosolic tyrosine kinases. Any mutation on the tyrosine kinases results in a variation in peptide substrate specificity, corroborating the need for catalytic specificity for selective signaling in human diseases.

A correction to the article "Endocrinization of FGFI Produces a Neomorphic and Potent Insulin Sensitizer" by Jae Myoung Suh, Johan W. Jonker and Regina Goetz published in "Nature" Vol 513 2014 issue is presented.