Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2.
The molecular adapter Grb7 is likely to be implicated in the development of certain cancer types. In this study we show that Grb7 binds the insulin receptors, when they are activated and tyrosine phosphorylated. This interaction is documented by two-hybrid experiments, GST pull-down assays and in vivo coimmunoprecipitations. In addition, our results argue in favor of a preferential association between Grb7 and the insulin receptors when compared to other tyrosine kinase receptors like the EGF receptor, the FGF receptor and Ret. Interestingly, Grb7 is not a substrate of the insulin receptor tyrosine kinase activity. Grb7 binds the activated tyrosine kinase loop of the insulin receptors. Two domains of Grb7 are implicated in the insulin receptor binding: the SH2 domain and the PIR (phosphotyrosine interacting region). The role of these two domains in the interaction with the insulin receptor was already reported for Grb10 and Grb14, the other members of the Grb7 family of proteins. However, the relative importance of these domains varies, considering the receptor and the Grb protein. These differences should be a determinant of the specificity of the receptor tyrosine kinase-Grbs binding, and thus of the implication of Grb7/10/14 in signal transduction.
Kasus-Jacobi
A
A
Endocrinologie Métabolisme et Développement, CNRS, UPR 1524, Meudon, France.
Béréziat
V
V
Perdereau
D
D
Girard
J
J
Burnol
A F
AF
D000818:Animals; D001665:Binding Sites; D019556:COS Cells / Q000378:metabolism; D003001:Cloning, Molecular; D005260:Female; D051382:GRB7 Adaptor Protein; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011506:Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D015003:Yeasts / Q000235:genetics; D018909:src Homology Domains
C495957:Grb7 protein, rat; D011506:Proteins; D011993:Recombinant Fusion Proteins; D051382:GRB7 Adaptor Protein; D011972:Receptor, Insulin