The neuropilin-like protein ESDN regulates insulin signaling and sensitivity

Abstract

Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilinlike protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulininduced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn Ϫ/Ϫ mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue.

Dynamic multi-site phosphorylation by Fyn and Abl drives the interaction between CRKL and the novel scaffolding receptors DCBLD1 and DCBLD2

“…DCBLD2 has been reported to be involved in vasculature remodeling [ 7 – 10 ] and insulin sensitivity [ 11 ], and is also up-regulated in a variety of cancers [ 12 – 14 ]. While relatively little is known about the specific molecular mechanisms by which DCBLD2 transduces or modulates signals, DCBLD2 has been shown to both positively and negatively regulate receptor tyrosine kinase (RTK) signaling [ 7 , 9 , 11 ]. DCBLD2-deficient mice show lower blood glucose levels and increased insulin-induced activation of MAPK and Akt [ 11 ].…”

“…While relatively little is known about the specific molecular mechanisms by which DCBLD2 transduces or modulates signals, DCBLD2 has been shown to both positively and negatively regulate receptor tyrosine kinase (RTK) signaling [ 7 , 9 , 11 ]. DCBLD2-deficient mice show lower blood glucose levels and increased insulin-induced activation of MAPK and Akt [ 11 ]. In cultured vascular smooth muscle cells, DCBLD2 knockdown similarly shows an increase in PDGF-induced stimulation of MAPK [ 15 ].…”

Single Nucleotide Polymorphism rs6942067 Is a Risk Factor in Young and in Non-Smoking Patients with HPV Negative Head and Neck Squamous Cell Carcinoma

“…The fact that DCBLD1 is a strong prognosis factor in HNSCC and experimentally associated with EGFR and MET suggests that DCBLD1 may play a critical role in HNSCC. Interestingly, DCBLD2, which is paralog to DCBLD1, has also been shown to be interacting with receptor tyrosine kinases such as EGFR, VEGFR, and INSR [28,49,50]. In the never-smoking lung adenocarcinoma study, the DCBLD1 susceptibility locus was associated with EGFR mutations in exons 19 and 21 (in the tyrosine kinase encoding region) [24,25].…”

Development and application of bioinformatic methods to analyze genome-wide expression and survival data from cancer patients

“…Por ejemplo, la proteína transmembrana DCBLD2 (ESDN), miembro de la familia de proteínas de tipo neuropilina, es un nuevo regulador de los efectos mitóticos y metabólicos de la insulina y modula la transducción de señales a través de la regulación de la interacción del receptor de insulina con sus proteínas adaptadoras. (Li et al, 2016). La importancia de la regulación de la insulina en la función de nuestro sistema digestivo es clara, y agrega un valor extra a la propuesta de DCBLD2 como marcador de supervivencia de CCR.…”

“…The analysis of the literature reveals some relevant observations. For example, the transmembrane protein DCBLD2 (ESDN), member of a family of neuropilin-like proteins, is a novel regulator of mitotic and metabolic eects of insulin, and it modulates signal transduction through regulation of the insulin receptor interaction with its adaptor proteins (Li et al, 2016). The importance of insulin regulation in the function of our digestive system is clear, and this adds extra value to the proposal of DCBLD2 as a CRC survival marker.…”