Formation of distinct signalling complexes involving phosphatidylinositol 3-kinase activity with stimulation of epidermal growth factor or insulin-like growth factor-I in human skin fibroblasts.
We recently described a better correlation of DNA synthesis with phosphatidylinositol (PI) 3-kinase than with mitogen-activated protein (MAP) kinase stimulated by insulin-like growth factor (IGF)-1 or epidermal growth factor (EGF) in human skin fibroblasts (Takahashi et al., 1997, Endocrinology 138:741-750). IGF-I-induced PI 3-kinase activation is generally mediated via insulin receptor ... substrate (IRS)-1, but EGF-induced PI 3-kinase activation is mediated by various signalling molecules such as ErbB3 and c-Cbl in different cells. We therefore investigated the mechanism regulating PI 3-kinase in human skin fibroblasts by comparing complexes involving PI 3-kinase when stimulated by IGF-I or EGF and found that p115 and p105, which were tyrosine-phosphorylated by EGF stimulation and associated with SHP-2, were also associated with the p85 subunit of PI 3-kinase by EGF. Anti-SHP-2 and anti-p85 subunits of PI 3-kinase antibodies did not coprecipitate tyrosine-phosphorylated EGF receptor or ErbB3; in addition, p115 and p105 appeared to be distinct from tyrosine-phosphorylated c-Cbl. Thus, tyrosine-phosphorylated p115 and p105 may provide a novel platform recruiting p85, which may simultaneously bind to SHP-2. In contrast, tyrosine phosphorylation of p115 or p 105 was undetectable by immunoblot with IGF-I stimulation, and PI 3-kinase activity was mediated via IRS-1 phosphorylated with IGF-I stimulation, little of which was associated with SHP-2. Thus, EGF and IGF-I cause formation of a distinct signalling complex which associates with p85 subunit of PI 3-kinase.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Enzyme Activation, Epidermal Growth Factor, Fibroblasts, GRB2 Adaptor Protein, Humans, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Precipitin Tests, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, SH2 Domain-Containing Protein Tyrosine Phosphatases, Signal Transduction, Skin, Tyrosine, src Homology Domains
Adaptor Proteins, Signal Transducing, Enzyme Activation, Epidermal Growth Factor, Fibroblasts, GRB2 Adaptor Protein, Humans, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Precipitin Tests, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, SH2 Domain-Containing Protein Tyrosine Phosphatases, Signal Transduction, Skin, Tyrosine, src Homology Domains
J. Cell. Physiol.
Date: Jan. 01, 1999
PubMed ID: 9886492
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