Activation of the Insulin-like Growth Factor Type 1 Receptor by Deletion of Amino Acids 870–905
| Autor: | Christian Sell, Shu Li, Hong Zhang, Henry B. Hoff |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Molecular Sequence Data
Mitogen-activated protein kinase kinase Tropomyosin receptor kinase C Receptor tyrosine kinase Cell Line Receptor IGF Type 1 MAP2K7 Mice Animals Amino Acid Sequence Phosphotyrosine Sequence Deletion Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 biology Cell Biology Protein-Tyrosine Kinases Phosphoproteins Molecular biology Enzyme Activation Calcium-Calmodulin-Dependent Protein Kinases ROR1 Insulin Receptor Substrate Proteins biology.protein Mitogen-Activated Protein Kinases Tyrosine kinase Platelet-derived growth factor receptor Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Experimental Cell Research. 243:326-333 |
| ISSN: | 0014-4827 |
| Popis: | We have created a deletion mutant of the insulin-like growth factor type 1 receptor (IGF-1 R) which lacks the 36 amino acids (aa) immediately N-terminal to the transmembrane domain (Delta870-905 IGF-1 R). This region has been reported to have a negative effect on the transforming potential of an avian sarcoma virus gag-IGF-1 R fusion protein. We have sought to determine whether this region plays a similar role in the intact IGF-1 R. Analysis of the tyrosine kinase activity of the Delta870-905 IGF-1 R shows that the mutant receptor is autophosphorylated without IGF-1 stimulation, indicating that the tyrosine kinase domain is constitutively active. In addition, processing of the receptor is decreased, resulting in accumulation of a high molecular weight proreceptor containing both alpha and beta-subunits. A well-characterized substrate of the IGF-1 R, IRS-1, is constitutively phosphorylated by the Delta870-905 IGF-1 R and phosphoinositide (PI) 3-kinase activity, which is normally activated by the phosphorylation of IRS-1 following IGF-1 stimulation, is increased even in the absence of IGF-1. A second intracellular signal pathway normally activated by IGF-1, the MAP kinase pathway, showed no increase in activity in the absence of IGF-1. The Delta870-905 IGF-1 R promoted cell proliferation only in the presence of IGF-1. We conclude that this deletion increases the basal activity of the IGF-1 receptor tyrosine kinase and activates PI 3-kinase, but is unable to stimulate MAP kinase in the absence of ligand. These results confirm those seen in the gag-IGF-1 R fusion protein and indicate that aa 870-905 exert a negative effect on the tyrosine kinase domain of the beta-subunit of the IGF-1 R. |
| Databáze: | OpenAIRE |
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