Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance

摘要: Insulin is an anabolic hormone with powerful metabolic effects. The events after insulin binds to its receptor are highly regulated and specific. Defining the key steps that lead specificity in signaling presents a major challenge biochemical research, but outcome should offer new therapeutic approaches for treatment of patients suffering from insulin-resistant states, including type 2 diabetes. The belongs large family growth factor receptors intrinsic tyrosine kinase activity. Following binding, undergoes autophosphorylation on multiple residues. This results activation phosphorylation substrate (IRS) proteins. These substrates commonly referred as docking proteins, since several other intracellular proteins bind phosphorylated substrates, thereby transmitting signal downstream. Like factors, uses resultant protein–protein interactions essential tools transmit compartmentalize signal. pivotal final cellular effect, such translocation vesicles containing GLUT4 glucose transporters pool plasma membrane, glycogen or protein synthesis, initiation specific gene transcription (Figure ​(Figure1).1). In this article, we review some our current understanding about early transduction through network IRS interacting mechanisms may modify especially obesity diabetes. Figure 1 Schematic illustration pathways action. phosphorylates Shc, which differentially various downstream PI3-kinase critical ... Protein–protein interactions Some best-characterized interaction domains involved PH (pleckstrin homology), PTB (phosphotyrosine binding), SH2, SH3 (1) (Table ​(Table1).1). Other, less-characterized (e.g., LIM, PDZ, NOTCH, WW) also prove be relevant (2). exist natural tertiary structure cases, created by posttranslational covalent modification protein. most common examples latter effects serine/threonine residues lipid prenylation fatty acid acylation Table 1 Classes signaling Figure ​Figure22 illustrates how transmitted using different types domains. domains, found interact receptor, charged headgroups phosphatidylinositides targeted preferentially membrane structures. target adjacent (3). recognize phosphotyrosine amino sequence asparagine-proline-any acid-phosphotyrosine (NPXpY), often present receptors, (4, 5). Figure 2 Protein–protein transduction. A typical contains domain, targets NPXpY motif β subunit ... Most partners contain Src homology (SH2) binding cassettes tend have higher affinity than patterns, making more rigid possible. SH2 consist roughly 100 acids, conserved pocket (FLAVRES sequence) (6). few acids COOH-terminal phosphotyrosine. at least four pYMXM motifs tyrosine-phosphorylated IRS-1. domain adaptor Grb-2 phosphatase SHP-2 sequences, pYVNI, pYIDL, pYASI sequences (1). addition these Crk (adaptor), Nck Fyn (tyrosine kinase), Csk their proline-rich consensus PXXP helix provide link between associated catalytic subunits (6). It kept mind many recognition elements target, it another protein, cytoskeletal structure, or, nucleotide sequence, amazing accuracy. Many one well elements. There numerous unknown undefined include 14-3-3 transforming simian virus 40 (SV40) T antigen, Ca2+ ATPase, integrin, discussed detail below. Lessons knockout animal models Evaluating sensitivity affects whole body glucohomeostasis has been diabetes research. One approach use disruption IRS-1, IRS-2. Targeted lethal days birth homozygous animals, whereas heterozygous animals almost no phenotype (161, 162). Disruption IRS-1 retarded (due IGF-1 resistance), only mild resistance impaired tolerance without (163, 164). IRS-2 leads resistance, case, there reduction β-cell mass, leading (165). Combination severe includes delayed onset similar human (166). pure form elevated levels. Interestingly, 40% mice develop diabetes, suggesting importance additional background genes. Tissue-specific gives detailed view homeostasis tissue-specific manner vivo. Muscle-specific (MIRKO) isolated skeletal muscles, level, near normal (74). Indeed, disturbances MIRKO mouse increased fat, triglycerides, slightly free cell–specific (βIRKO) MIRKO, severely loss first-phase secretion test (167). models demonstrate serves important role function suggest level contribute altered diabetes. Additional data help us clarify define defects responsible