LMBD1 protein serves as a specific adaptor for insulin receptor internalization
Journal
Journal of Biological Chemistry
Journal Volume
288
Journal Issue
45
Pages
32424-32432
Date Issued
2013
Author(s)
Abstract
Energy homeostasis is crucial for maintaining normally functioning cells; disturbances in this balance often cause various diseases. The limb region 1 (LMBR1) domain containing 1 gene (lmbrd1) encodes the LMBD1 protein that possesses 9 putative transmembrane domains. LMBD1 has been suggested to be involved in the lysosome in aiding the export of cobalamin. In this study, we determined that LMBD1 plays a regulatory role in the plasma membrane. A micro-positron emission tomography analysis showed that a single-allele knock-out of lmbrd1 increased the 18F-fluorodeoxyglucose uptake in murine hearts. In addition, the knockdown of lmbrd1 resulted in an up-regulated signaling of the insulin receptor (IR) and its downstream signaling molecule, Akt. Confocal and live total internal reflection fluorescence microscopy showed that LMBD1 co-localized and co-internalized with clathrin and the IR, but not with the transferrin receptor. The results of the mutation analysis and phenotypic rescue experiments indicate that LMBD1 interacts with adaptor protein-2 and is involved in the unique clathrinmediated endocytosis of the IR. LMBD1 selectively interacts with the IR. The knockdown of lmbrd1 attenuated IR endocytosis, resulting in the perturbation of the IR recycling pathway and consequential enhancement of the IR signaling cascade. In summary, LMBD1 plays an imperative role in mediating and regulating the endocytosis of the IR. ? 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
Other Subjects
Emission tomography; Energy homeostasis; F-fluorodeoxyglucose; Recycling pathways; Signaling molecules; Total internal reflection fluorescence microscopy; Trans-membrane domains; Transferrin receptors; Activation analysis; Cell membranes; Insulin; Molecular biology; Positron emission tomography; Refractive index; Proteins; adaptor protein; adaptor protein 2; clathrin; fluorodeoxyglucose f 18; insulin receptor; membrane protein; protein kinase B; protein LMBD1; transferrin receptor; unclassified drug; animal cell; article; controlled study; endocytosis; fluorescence microscopy; gene; internalization; Lmbrd1 gene; mouse; newborn; nonhuman; positron emission tomography; priority journal; protein function; protein localization; protein protein interaction; rat; signal transduction; upregulation; Akt; Antisense RNA; Cell Signaling; Cell Surface Receptor; Confocal Microscopy; Endocytosis; Flow Cytometry; Glucose Metabolism; In Vivo Imaging; Insulin; Adaptor Protein Complex 2; Animals; Cell Line; Clathrin; Endocytosis; Fluorodeoxyglucose F18; Gene Knockdown Techniques; Humans; Mice; Mice, Mutant Strains; Myocardium; Nucleocytoplasmic Transport Proteins; Positron-Emission Tomography; Proto-Oncogene Proteins c-akt; Radiopharmaceuticals; Rats; Receptor, Insulin; Signal Transduction
Type
journal article