System-wide Investigation of ErbB4 Reveals 19 Sites of Tyr Phosphorylation that Are Unusually Selective in Their Recruitment Properties

Program in Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Chemistry & Biology (Impact Factor: 6.65). 09/2008; 15(8):808-17. DOI: 10.1016/j.chembiol.2008.07.006
Source: PubMed


The first three members of the ErbB family of receptor tyrosine kinases activate a wide variety of signaling pathways and are frequently misregulated in cancer. Much less is known about ErbB4. Here we use tandem mass spectrometry to identify 19 sites of tyrosine phosphorylation on ErbB4, and protein microarrays to quantify biophysical interactions between these sites and virtually every SH2 and PTB domain encoded in the human genome. Our unbiased approach highlighted several previously unrecognized interactions and led to the finding that ErbB4 can recruit and activate STAT1. At a systems level, we found that ErbB4 is much more selective than the other ErbB receptors. This suggests that ErbB4 may enable ErbB2 and ErbB3 to signal independently of EGFR under normal conditions, and provides a possible explanation for the protective properties of ErbB4 in cancer.

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    • "Similar to the SH2 domain, PTB domains may bind tyrosine phosphorylation sites in cellular proteins. Proteomic studies have revealed that the two domain families may in fact target overlapping pTyr sites with micromolar affinities [57-59,113]. However, unlike SH2 domains, the specificity of a PTB domain is primarily focused towards amino acids N-terminal to the pTyr residue in a peptide, most commonly in an NPXpY or NPXY sequence motif [114]. "
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