A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R.
Receptor tyrosine kinases transmit and process extracellular cues by recruiting intracellular signaling proteins to sites of tyrosine phosphorylation. Using protein microarrays comprising virtually every human SH2 and PTB domain, we generated quantitative protein interaction maps for three well-studied receptors--EGFR, FGFR1 and IGF1R--using phosphopeptides derived from every intracellular tyrosine residue on each receptor, regardless of whether or not they are phosphorylated in vivo. We found that, in general, peptides derived from physiological sites of tyrosine phosphorylation bind to substantially more SH2 or PTB domains than do peptides derived from nonphysiological sites, supporting the idea that kinases and interaction domains co-evolve and suggesting that new sites arise predominantly through selection favoring advantageous interactions, rather than through selection disfavoring unwanted interactions. We also found substantial qualitative overlap in the recruitment profiles of these three receptors, suggesting that their different biological effects arise, at least in part, from quantitative differences in their affinities for the proteins they recruit.
Kaushansky
Alexis
A
Program in Molecular and Cellular Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Gordus
Andrew
A
Chang
Bryan
B
Rush
John
J
MacBeath
Gavin
G
D016000:Cluster Analysis; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism*; D018909:src Homology Domains
D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D066246:ErbB Receptors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017526:Receptor, IGF Type 1