Signalling through the ERBB/HER receptors is intricately involved in human cancer and already serves as a target for several cancer drugs. Because of its inherent complexity, it is useful to envision ERBB signalling as a bow-tie-configured, evolvable network, which shares modularity, redundancy and control circuits with robust biological and engineered systems. Because network fragility is an inevitable trade-off of robustness, systems-level understanding is expected to generate therapeutic opportunities to intercept aberrant network activation.

EGF–ERBB signalling: towards the systems level

Ample data indicate that mutant p53 proteins not only lose their tumour suppressive functions, but also gain new abilities that promote tumorigenesis. Moreover, recent studies have modified our view of mutant p53 proteins, portraying them not as inert mutants, but rather as regulated proteins that influence the cancer cell transcriptome and phenotype. This influence is clinically manifested as association of TP53 mutations with poor prognosis and drug resistance in a growing array of malignancies. Here, we review recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association, with a focus on the clinical implications of these findings.

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When mutants gain new powers: news from the mutant p53 field

The year 2007 marks exactly two decades since Human Epidermal Growth Factor Receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer. This finding established the HER2 oncogene hypothesis for the development of some human cancers. The subsequent two decades have brought about an explosion of information about the biology of HER2 and the HER family. An abundance of experimental evidence now solidly supports the HER2 oncogene hypothesis and etiologically links amplification of the HER2 gene locus with human cancer pathogenesis. The molecular mechanisms underlying HER2 tumorigenesis appear to be complex and a unified mechanistic model of HER2-induced transformation has not emerged. Numerous hypotheses implicating diverse transforming pathways have been proposed and are individually supported by experimental models and HER2 may indeed induce cell transformation through multiple mechanisms. Here I review the evidence supporting the oncogenic function of HER2, the mechanisms that are felt to mediate its oncogenic functions, and the evidence that links the experimental evidence with human cancer pathogenesis.

The oncogene HER2; Its signaling and transforming functions and its role in human cancer pathogenesis

ErbB receptors and signaling pathways in cancer

Researchers in many biological areas now routinely characterize proteins by mass spectrometry. Among the many formats for quantitative proteomics, stable-isotope labelling by amino acids in cell culture (SILAC) has emerged as a simple and powerful one. SILAC removes false positives in protein-interaction studies, reveals large-scale kinetics of proteomes and - as a quantitative phosphoproteomics technology - directly uncovers important points in the signalling pathways that control cellular decisions.

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Functional and quantitative proteomics using SILAC

Interactions between short modified peptide motifs and modular protein domains are central events in cell signal-transduction. We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. We identified STAT5 as a direct binding partner to EGFR and ErbB4 and discovered new recognition motifs for Shc and STAT5. The overall pattern of interaction partners of EGFR and ErbB4 suggests similar roles during signaling through their respective ligands. Phosphorylation kinetics of several tyrosine resides was measured by mass spectrometry and correlated with interaction partner preference. Our results demonstrate that system-wide mapping of peptide-protein interactions sites is possible, and suggest shared and unique roles of ErbB-receptor family members in downstream signaling.

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Phosphotyrosine interactome of the ErbB‐receptor kinase family

Post-translational modification (PTM) is crucial for various cell signaling pathways and biological processes. However, the interactions between PTMs (PTM cross-talk) or PTMs and other sites (PTM mutation) are still in there infancy, with many challenges remaining unexplored. Since PTMs play a fundamental role in cell biology, many mutations cause abnormalities in many PTM sites and affect many human diseases. In this research, we propose an algorithm to improve PTM sites and PTM sites (PTM cross-talk) prediction and to study the interaction between PTM sites and mutation sites (PTM mutation). In addition to the primary network features of three-dimensional protein structure and sequence features, the dynamic features based on ENMs (elastic network models) are also used to improve model performance. Through feature selection, we reserved 48 features and developed a predictor for predicting PTM cross-talk and mutation. According to the evaluation based on PTM cross-talk, the area under the curve of our best prediction model reaches 0.911, which exceeds the state-of-art-model PCTpred. Based on the evaluation of PTM mutation, our prediction model is highly reliable, with an AUC score of 0.935. Even with the removal of the distance, the performance of our model (which is the most excellent model of the nine models, Random Forest model) is relatively stable. 

Lei Deng

Papers

Phosphotyrosine interactome of the ErbB‐receptor kinase family

Prediction of post-translational modification cross-talk and mutation within proteins via imbalanced learning