title: Insulin receptor activation with transmembrane domain ligands.
abstract: Complementary surfaces are buried when peptide hormones, growth factors, or cytokines bind and activate cellular receptors. Although these extended surfaces provide high affinity and specificity to the interactions, they also present great challenges to the design of small molecules that might either mimic or antagonize the process. We show that the insulin receptor (IR) and downstream signals can be activated by targeting a site outside of its ligand-binding domain. A 24-residue peptide having the IR transmembrane (TM) domain sequence activates IR, but not related growth factor receptors, through specific interactions with the receptor TM domain. Like insulin-dependent activation, IR-TM requires that IR have a competent ATP-binding site and kinase activation loop. IR-TM also activates mutated receptors from patients with severe insulin resistance, which do not respond to insulin. These results show that IR can be activated through a pathway that bypasses its canonical ligand-binding domain.
authors.affiliation: From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215 jongsoon.lee@joslin.harvard.edu.
authors.forename: Jongsoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Masaya
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Giulio R
authors.initials: GR
authors.lastname: Romeo
authors.affiliation: From the Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215 steven.shoelson@joslin.harvard.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D011972:Receptor, Insulin
keywords: Insulin; Insulin Receptor; Peptide Hormone; Peptide Ligand; Receptor Activation; Receptor Tyrosine Kinase; Transmembrane Domain