SH-PTP2/Syp SH2 domain binding specificity is defined by direct interactions with platelet-derived growth factor beta-receptor, epidermal growth factor receptor, and insulin receptor substrate-1-derived phosphopeptides.

Case, Randi D.; Piccione, E.; Wolf, G.; Benett, A.M.; Lechleider, Robert J.; Neel, Benjamin G.; Shoelson, Steven E.

doi:10.1016/s0021-9258(17)34083-8

Cited by 130 publications

(19 citation statements)

References 48 publications

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“…Structural studies have shown that recognition can occur as far upstream as the À7 position of a phosphopeptide for some PTB domains [32][33][34] and as far downstream as the +5 position of a peptide for some SH2 domains. [35][36][37] To ensure an accurate analysis of all domains, we synthesized peptides with sequences that include nine residues upstream and seven residues downstream of the pY (Table 1). To visualize peptides that are bound by SH2 and PTB domains, we labeled each peptide on its amino-terminus with 5-(and-6)-carboxytetramethylrhodamine [5(6)-TAMRA].…”

Section: Quantitative Protein Interaction Maps Using Protein Microarraysmentioning

confidence: 99%

A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R

et al. 2008

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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 wellstudied 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.

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Section: Quantitative Protein Interaction Maps Using Protein Microarraysmentioning

confidence: 99%

A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R

et al. 2008

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“…Similar resu lts were obtai ned in two independent experiments. X-VallLeulIle is selected by the Sy p NH 2 -term in al SH2 domain from a degen erate pep tid e lib rary (45). It has a lso shown t hat the Sy p SH2 domains recognize a YTAV seque nce in th e (3 su bun it pla telet-derived gro wt h fa ctor receptor (30, 3 1).…”

Section: Epo Receptor Signal Transduction Protein Tyrosine Phosphatasementioning

confidence: 99%

Involvement of SH2-containing Phosphotyrosine Phosphatase Syp in Erythropoietin Receptor Signal Transduction Pathways

Tauchi

Feng

Shen

et al. 1995

Journal of Biological Chemistry

149

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Erythropoietin (Epo) regulates the proliferation and differentiation of erythroid precursors. The phosphorylation of proteins at tyrosine residues is critical in the growth signaling induced by Epo. This mechanism is regulated by the activities of both protein-tyrosine kinases and protein tyrosine phosphatases. The discovery of phosphotyrosine phosphatases that contain SH2 domains suggests roles for these molecules in growth factor signaling pathways. We found that Syp, a phosphotyrosine phosphatase, widely expressed in all tissues in mammals became phosphorylated on tyrosine after stimulation with Epo in M07ER cells engineered to express high levels of human EpoR. Syp was complexed with Grb2 in Epo-stimulated M07ER cells. Direct binding between Syp and Grb2 was also observed in vitro. Furthermore, Syp appeared to bind directly to tyrosine-phosphorylated EpoR in M07ER cells. Both NH2-terminal and COOH-terminal SH2 domains of Syp, made as glutathione S-transferase fusion proteins, were able to bind to the tyrosine-phosphorylated EpoR in vitro. These results suggest that Syp may be an important signaling component downstream of the EpoR and may regulate the proliferation and differentiation of hematopoietic cells.

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“…Kay reported that the sequence could be shortened at the C-terminus down to residue +5 and at the N-terminus down to residue −2, without any loss of affinity. By contrast, Case observed a significant decrease in affinity by shortening the sequence from SLN-pY-IDLDLVKD to LN-pY-IDLDLV. Our previous study clearly indicated that residues −2 to +5 are the most important for the interaction .…”

Section: Resultsmentioning

confidence: 79%

“…Hydrophobic residues are required at positions +1, +3, and +5 of the phosphopeptide sequence, but aromatic residues are present in some natural high-affinity binding sequences, at position +5 only. ,,,, The crystallographic structures of some of these complexes ,, show that an aromatic side chain can be accommodated by a relatively large hydrophobic pocket and that the peptide residue 5 interacts with the BG and EF loops of the domain, which are important for binding specificity. , Finally, a preference for aromatic residues at position +5 has been indicated by several peptide library studies. ,− …”

Section: Resultsmentioning

confidence: 99%

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein–Protein Interactions

et al. 2021

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We developed a new class of inhibitors of protein–protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2–20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein–protein interactions in the function of SHP2.

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SH-PTP2/Syp SH2 domain binding specificity is defined by direct interactions with platelet-derived growth factor beta-receptor, epidermal growth factor receptor, and insulin receptor substrate-1-derived phosphopeptides.

Cited by 130 publications

References 48 publications

A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R

A quantitative study of the recruitment potential of all intracellular tyrosine residues on EGFR, FGFR1 and IGF1R

Involvement of SH2-containing Phosphotyrosine Phosphatase Syp in Erythropoietin Receptor Signal Transduction Pathways

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein–Protein Interactions

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