17344070

pubmed:Citation

8

The exon 16-encoded juxtamembrane (JM) domain of human insulin receptor (hIR) harbors the NPEY motif which couples the insulin-activated hIR kinase to downstream signal transduction molecules. We sought to determine if signal transduction requires the entire exon 16-encoded 22-amino acid JM domain. Transfected CHO cells were generated stably expressing either the wild-type hIR (hIR-WT) or two mutant hIRs (hIRDeltaEx16 in which the JM domain was deleted, and hIRrosJM in which the deleted segment was replaced by the corresponding domain of v-ros protein). The mutant hIRDeltaEx16 and hIRrosJM exhibited similar insulin-binding as the hIRWT. Insulin internalization and insulin dose-response experiments toward activation of downstream signal transduction molecules demonstrated that: i) the presence of intact hIR-JM domain which harbors the NPEY motif is essential for Shc phosphorylation but not for IRS-1 phosphorylation; ii) insulin signal transduction can occur independent of the JM domain of hIR and without participation of the NPEY motif; iii) engagement of this putative alternative downstream signal transduction is Shc independent and is dependent on insulin concentration; and iv) insulin internalization does not necessarily require the hIR specific aa sequence of the JM domain which can be partially substituted by the JM domain of the v-ros tyrosine kinase.

eng

IM

MEDLINE

1065-6995

Print

NLM

815-24

pubmed-meshheading:17344070-Adaptor Proteins, Signal Transducing, pubmed-meshheading:17344070-Animals, pubmed-meshheading:17344070-Antigens, CD, pubmed-meshheading:17344070-CHO Cells, pubmed-meshheading:17344070-Cell Line, pubmed-meshheading:17344070-Cricetinae, pubmed-meshheading:17344070-Cricetulus, pubmed-meshheading:17344070-Humans, pubmed-meshheading:17344070-Insulin, pubmed-meshheading:17344070-Insulin Receptor Substrate Proteins, pubmed-meshheading:17344070-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:17344070-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:17344070-Phosphoproteins, pubmed-meshheading:17344070-Phosphorylation, pubmed-meshheading:17344070-Protein Structure, Tertiary, pubmed-meshheading:17344070-Protein-Tyrosine Kinases, pubmed-meshheading:17344070-Proto-Oncogene Proteins, pubmed-meshheading:17344070-Proto-Oncogene Proteins c-akt, pubmed-meshheading:17344070-Receptor, Insulin, pubmed-meshheading:17344070-Shc Signaling Adaptor Proteins, pubmed-meshheading:17344070-Signal Transduction

Human insulin receptor juxtamembrane domain independent insulin signaling.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural