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Autoinhibition of the insulin‐like growth factor I receptor by the juxtamembrane region
Author(s) -
Craddock Barbara P.,
Cotter Christopher,
Miller W. Todd
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.06.014
Subject(s) - autophosphorylation , insulin like growth factor 1 receptor , tropomyosin receptor kinase c , insulin receptor , receptor tyrosine kinase , biology , tyrosine kinase , irs2 , microbiology and biotechnology , tropomyosin receptor kinase b , kinase , receptor , biochemistry , signal transduction , platelet derived growth factor receptor , protein kinase a , growth factor , insulin , endocrinology , insulin resistance , neurotrophic factors
The juxtamembrane (JM) regions of several receptor tyrosine kinases are involved in autoinhibitory interactions that maintain the low basal activity of the receptors; mutations can give rise to constitutive kinase activity and signaling. In this report, we show that the JM region of the human insulin‐like growth factor I receptor (IGF1R) plays a role in kinase regulation. We mutated JM residues that were conserved in this subfamily of receptor tyrosine kinases, and expressed and purified the cytoplasmic domains using the Sf9/baculovirus system. We show that a kinase‐proximal mutation (Y957F) and (to a lesser extent) a mutation in the central part of the JM region (N947A) increase the autophosphorylation activity of the kinase. Steady‐state kinetic measurements show the mutations cause an increase in V max for phosphorylation of peptide substrates. When the holoreceptors were expressed in fibroblasts derived from IGF1R‐deficient mice, the Y957F mutation led to a large increase in basal and in IGF1‐stimulated receptor autophosphorylation. Together, these data demonstrate that the JM region of IGF1R plays an important role in limiting the basal activity of the receptor.