Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins. Proc Natl Acad Sci USA

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2003; 100(20):11267-72. DOI: 10.1073/pnas.1934711100
Source: PubMed


Signal transduction pathways are typically controlled by protein-protein interactions, which are mediated by specific modular domains. One hypothetical use of such interaction domains is to generate new signaling pathways and networks during eukaryotic evolution, through the joining of distinct binding modules in novel combinations. In this manner, new polypeptides may be formed that make innovative connections among preexisting proteins. Adaptor proteins are specialized signaling molecules composed exclusively of interaction domains, that frequently link activated cell surface receptors to their intracellular targets. Receptor tyrosine kinases (RTKs) recruit adaptors, such as Grb2 and ShcA, that activate signaling pathways involved in growth and survival, whereas death receptors bind adaptors, such as Fadd, that promote apoptosis. To test the ability of interaction domains to create new signaling pathways, we have fused the phosphotyrosine recognition domains of Grb2 (Scr homology 2 domain) or ShcA (phosphotyrosine-binding domain) to the death effector domain of Fadd. We find that these chimeric adaptors can reroute mitogenic or transforming RTK signals to induce caspase activation and cell death. These hybrid adaptors can be used to selectively kill oncogenic cells in which RTK activity is deregulated.

Download full-text


Available from: Perry L Howard
  • Source
    • "The Omics technologies have facilitated the discovery of core signaling pathways from the database of Pathway Commons, KEGG, Pathway Recognition Algorithm, and Ingenuity [77]. For example, the affected receptor tyrosine kinase (RTK), which is involved in the signaling pathway of the cell proliferation altered by phosphatidylinositide 3-kinases (PI-3K), have been identified in breast cancer, colorectal cancer, glioblastoma, and lung cancer [12] [36] [48] [58]. Another good example is the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) that can control DNA transcription, regulate immune response to infection , and regulate cellular response to stimuli [44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is a complex invasive genetic disease that causes significant mortality rate worldwide. Protein-based biopharmaceuticals have significantly extended the lives of millions of cancer patients. This article reviews the biological function and application of targeted anticancer biopharmaceuticals. We first discuss the specific antigens and core pathways that are used in the development of targeted cancer therapy. The innovative monoclonal antibodies, non-antibody proteins, and small molecules targeting these antigens or pathways are then reviewed. Finally, the current challenges in anticancer biopharmaceuticals development and the potential solutions to address these challenges are discussed.
    Full-text · Article · Jul 2014 · Cancer Letters
  • Source
    • "Early work on the modular interaction domains such as SH2 and SH3 laid the groundwork for much of modern synthetic biology. Pawson and co-workers showed that single residue alterations in the specificity pocket of an SH2 domain can not only change the binding properties of the domain in vitro but also it's biological activity in an intact organism [33] and that the fusion of the SH2 domain of adaptor proteins to a death effector domain of the FADD adaptor rerouted mitogenic growth factor signalling to induce caspase activation and cell death [34]. Such chimeric adaptors could be used to selectively kill oncogenic cells in which RTK activity is deregulated, suggesting the potential for rewiring cancer cells using synthetic biology approaches as a means of therapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The serendipitous discovery of the SH2 domain unleashed a sea-change in our conceptual molecular understanding of protein function. The reductionist approaches that followed from the recognition of modular protein interaction domains transformed our understanding of cellular signal transduction systems, how they evolve and how they may be manipulated. We now recognize thousands of conserved protein modules - many of which have been described in structure and function, implicated in disease, or underlie targeted therapeutics. The reductionist study of isolated protein modules has enabled the reconstruction of the protein interaction networks that underlie cellular signalling. Protein modules themselves are becoming tools to probe cellular activation states and identify key interactions hubs in both normal and diseased cells and the concept of protein modularity is central to the field of synthetic biology. This brief word of introduction serves to highlight the historical impact of the very powerful idea of protein modules and sets the stage for the exciting on-going discoveries discussed in this issue.
    Full-text · Article · May 2012 · FEBS letters
  • Source
    • "For example, the interaction between the pYDEV motif within the enteropathogenic Escherichia coli protein Tir and the Nck1 SH2 domain leads to drastic cytoskeletal rearrangements [75]. In a related vein, a chimeric Grb2 SH2 domain FADD death effector domain (DED) fusion is capable of switching cellular responses so that mitogenic signals result in activation of an apoptotic pathway [76] thereby connecting distinct signaling pathways together via novel synthetic domain associations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Modular protein interaction domains (PIDs) that recognize linear peptide motifs are found in hundreds of proteins within the human genome. Some PIDs such as SH2, 14-3-3, Chromo, and Bromo domains serve to recognize posttranslational modification (PTM) of amino acids (such as phosphorylation, acetylation, methylation, etc.) and translate these into discrete cellular responses. Other modules such as SH3 and PSD-95/Discs-large/ZO-1 (PDZ) domains recognize linear peptide epitopes and serve to organize protein complexes based on localization and regions of elevated concentration. In both cases, the ability to nucleate-specific signaling complexes is in large part dependent on the selectivity of a given protein module for its cognate peptide ligand. High-throughput (HTP) analysis of peptide-binding domains by peptide or protein arrays, phage display, mass spectrometry, or other HTP techniques provides new insight into the potential protein-protein interactions prescribed by individual or even whole families of modules. Systems level analyses have also promoted a deeper understanding of the underlying principles that govern selective protein-protein interactions and how selectivity evolves. Lastly, there is a growing appreciation for the limitations and potential pitfalls associated with HTP analysis of protein-peptide interactomes. This review will examine some of the common approaches utilized for large-scale studies of PIDs and suggest a set of standards for the analysis and validation of datasets from large-scale studies of peptide-binding modules. We will also highlight how data from large-scale studies of modular interaction domain families can provide insight into systems level properties such as the linguistics of selective interactions.
    Full-text · Article · May 2012 · Proteomics
Show more