Abstract
Mutation and overexpression of receptor tyrosine kinases or the proteins they regulate serve as oncogenic drivers in diverse cancers. To better understand receptor tyrosine kinase signaling and its link to oncogenesis, we used protein microarrays to systematically and quantitatively measure interactions between virtually every SH2 or PTB domain encoded in the human genome and all known sites of tyrosine phosphorylation on 40 receptor tyrosine kinases and on most of the SH2 and PTB domain-containing adaptor proteins. We found that adaptor proteins, like RTKs, have many high affinity bindings sites for other adaptor proteins. In addition, proteins that drive cancer, including both receptors and adaptor proteins, tend to be much more highly interconnected via networks of SH2 and PTB domain-mediated interactions than nononcogenic proteins. Our results suggest that network topological properties such as connectivity can be used to prioritize new drug targets in this well-studied family of signaling proteins.
Highlights
Receptor Tyrosine Kinase (RTK)1 signaling networks evolved in Metazoans to process extracellular cues and elicit cellular responses such as differentiation, proliferation or migration
Binding of phosphatidylinositol 3-kinase (PI3KR1, p85) to pTyr612 of IRS1 initiates signaling through the PI3K/AKT cascade in cells exposed to insulin or insulin-like growth factors [5]
Data Collection—We started by compiling a list of known sites of tyrosine phosphorylation on human RTKs and on all SH2 and PTB domain-containing proteins listed in the PhosphoSitePlus database [42]
Summary
Receptor Tyrosine Kinase (RTK)1 signaling networks evolved in Metazoans to process extracellular cues and elicit cellular responses such as differentiation, proliferation or migration. We use this approach to systematically quantify, on a nearly proteome-wide level, interactions between SH2 or PTB domains and known sites of tyrosine phosphorylation on both human RTKs and the adaptor proteins themselves.
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