Abstract
Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase Cα resulted in a subsequent inhibition of the ligand- stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase Cα inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase Cα, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase Cα in the cells that served as a source of the substrates. Finally, the insulin- like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase Cα. These results indicate that the ability of activated protein kinase Cα to antagonize signaling by the human insulin receptor is shared by the other members of the insulin receptor family despite their considerable differences in amino acid sequence. Moreover, the present study shows that this antagonism is exerted at a very early step, the initial tyrosine phosphorylation of three distinct endogenous substrates. Finally, the present study indicates that this inhibition is not caused by an increased Ser/Thr phosphorylation of these two substrates.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 21600-21605 |
| Number of pages | 6 |
| Journal | Journal of Biological Chemistry |
| Volume | 270 |
| Issue number | 37 |
| DOIs | |
| State | Published - 1995 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
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Activation of protein kinase Cα inhibits signaling by members of the insulin receptor family. / Danielsen, A. G.; Liu, Feng; Hosomi, Y.; Shii, K.; Roth, R. A.
In: Journal of Biological Chemistry, Vol. 270, No. 37, 1995, p. 21600-21605.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of protein kinase Cα inhibits signaling by members of the insulin receptor family
AU - Danielsen, A. G.
AU - Liu, Feng
AU - Hosomi, Y.
AU - Shii, K.
AU - Roth, R. A.
PY - 1995
Y1 - 1995
N2 - Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase Cα resulted in a subsequent inhibition of the ligand- stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase Cα inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase Cα, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase Cα in the cells that served as a source of the substrates. Finally, the insulin- like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase Cα. These results indicate that the ability of activated protein kinase Cα to antagonize signaling by the human insulin receptor is shared by the other members of the insulin receptor family despite their considerable differences in amino acid sequence. Moreover, the present study shows that this antagonism is exerted at a very early step, the initial tyrosine phosphorylation of three distinct endogenous substrates. Finally, the present study indicates that this inhibition is not caused by an increased Ser/Thr phosphorylation of these two substrates.
AB - Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase Cα resulted in a subsequent inhibition of the ligand- stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase Cα inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase Cα, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase Cα in the cells that served as a source of the substrates. Finally, the insulin- like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase Cα. These results indicate that the ability of activated protein kinase Cα to antagonize signaling by the human insulin receptor is shared by the other members of the insulin receptor family despite their considerable differences in amino acid sequence. Moreover, the present study shows that this antagonism is exerted at a very early step, the initial tyrosine phosphorylation of three distinct endogenous substrates. Finally, the present study indicates that this inhibition is not caused by an increased Ser/Thr phosphorylation of these two substrates.
UR - http://www.scopus.com/inward/record.url?scp=0029097626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029097626&partnerID=8YFLogxK
U2 - 10.1074/jbc.270.37.21600
DO - 10.1074/jbc.270.37.21600
M3 - Article
VL - 270
SP - 21600
EP - 21605
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 37
ER -