ArticleProceedings of the National Academy of Sciences of the United States of America2013
Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 105 citations in OpenAlex.
- Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state.Molecular cell · 2026Article
- Protein Engineering-Enabled Cryo-EM Investigation of Small GTPases.Journal of molecular biology · 2026Article
- Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state.bioRxiv : the preprint server for biology · 2026Article
- Decoding C‑SH2 Domain/Peptide Interactions in SH2 Domain-Containing Tyrosine Phosphatase 2: A Molecular Framework for Rational Inhibitor Design.ACS omega · 2026Article
- Modifying inhibitor specificity for homologous enzymes by machine learning.The FEBS journal · 2026Article
- Utilizing Engineered Monobodies for the Electrochemical Quantification of Lysozyme.Analytical chemistry · 2025Article
- Synthetic protein degradation circuits using programmable cleavage and ligation by Sortase A.Nature communications · 2025Article
- Design of Cell-Penetrating Domain Antibodies via a Genetically Encoded β-Lactam Amino Acid.Angewandte Chemie (International ed. in English) · 2025Article
- Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase.Nature communications · 2024Article
- Generating and validating renewable affimer protein binding reagents targeting SH2 domains.Scientific reports · 2024Article
- Determination of promising inhibitors for N-SH2 domain of SHP2 tyrosine phosphatase: an in silico study.Molecular diversity · 2024Article
- Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes.Communications biology · 2024Article
- Complex Roles ofAnnual review of cancer biology · 2024Article
- Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.Nature communications · 2024Article
- Improving the pharmacokinetics, biodistribution and plasma stability of monobodies.Frontiers in pharmacology · 2024Article
- Conformation state-specific monobodies regulate the functions of flexible proteins through conformation trapping.Protein science : a publication of the Protein Society · 2023Article
- Structures of a FtsZ single protofilament and a double-helical tube in complex with a monobody.Nature communications · 2023Article
- Monobody Inhibitor Selective to the Phosphatase Domain of SHP2 and its Use as a Probe for Quantifying SHP2 Allosteric Regulation.Journal of molecular biology · 2023Article
- Orthogonal Crosslinking: A Strategy to Generate Novel Protein Topology and Function.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Setting sail: Maneuvering SHP2 activity and its effects in cancer.Advances in cancer research · 2023Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
The dysregulated tyrosine kinase BCR-ABL causes chronic myelogenous leukemia in humans and forms a large multiprotein complex that includes the Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2). The expression of SHP2 is necessary for BCR-ABL-dependent oncogenic transformation, but the precise signaling mechanisms of SHP2 are not well understood. We have developed binding proteins, termed monobodies, for the N- and C-terminal SH2 domains of SHP2. Intracellular expression followed by interactome analysis showed that the monobodies are essentially monospecific to SHP2. Two crystal structures revealed that the monobodies occupy the phosphopeptide-binding sites of the SH2 domains and thus can serve as competitors of SH2-phosphotyrosine interactions. Surprisingly, the segments of both monobodies that bind to the peptide-binding grooves run in the opposite direction to that of canonical phosphotyrosine peptides, which may contribute to their exquisite specificity. When expressed in cells, monobodies targeting the N-SH2 domain disrupted the interaction of SHP2 with its upstream activator, the Grb2-associated binder 2 adaptor protein, suggesting decoupling of SHP2 from the BCR-ABL protein complex. Inhibition of either N-SH2 or C-SH2 was sufficient to inhibit two tyrosine phosphorylation events that are critical for SHP2 catalytic activity and to block ERK activation. In contrast, targeting the N-SH2 or C-SH2 revealed distinct roles of the two SH2 domains in downstream signaling, such as the phosphorylation of paxillin and signal transducer and activator of transcription 5. Our results delineate a hierarchy of function for the SH2 domains of SHP2 and validate monobodies as potent and specific antagonists of protein-protein interactions in cancer cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.