Cells are continuously exposed to diverse stimuli ranging from soluble endocrine and paracrine factors, to signaling molecules on neighboring cells. It is of great importance that these extracellular signals are correctly interpreted by the cell, in order to achieve an appropriate developmental or proliferative response. Receptors of the tyrosine kinase family play pivotal roles in this process. By binding to specific peptide ligands they are able to integrate these external stimuli with internal signal transduction pathways, contributing in this fashion to the ability of the cell to respond correctly to its environment. In this review, we will concentrate on the role of ErbB receptors as normal signal transducers and their contribution to the process of malignant transformation during tumor development.

ErbB proteins belong to subclass I of the superfamily of receptor tyrosine kinases (RTKs). There are four members of the ErbB family: epidermal growth factor (EGF) receptor (also termed ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4. We will refer to them, henceforth, as the ErbB receptors. All family members have in common an extracellular ligand‐binding domain, a single membrane‐spanning region and a cytoplasmic protein tyrosine kinase domain. A family of ligands, the EGF‐related peptide growth factors, bind the extracellular domain of ErbB receptors leading to the formation of both homo‐ and heterodimers. Dimerization consequently stimulates the intrinsic tyrosine kinase activity of the receptors and triggers autophosphorylation of specific tyrosine residues within the cytoplasmic domain. These phosphorylated residues serve as docking sites for signaling molecules involved in the regulation of intracellular signaling cascades. Ultimately, downstream effects on gene expression determine the biological response to receptor activation.

ErbB receptors are expressed in a variety of tissues of epithelial, mesenchymal and neuronal origin, where they play fundamental roles in development, proliferation and differentiation. Moreover, deregulated expression of ErbB receptors, in particular ErbB1 and ErbB2, has …

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The ErbB signaling network: receptor heterodimerization in development and cancer

The emergence of tissue engineering raises new possibilities for the study of complex physiological and pathophysiological processes in vitro. Many tools are now available to create 3D tissue models in vitro, but the blueprints for what to make have been slower to arrive. We discuss here some of the 'design principles' for recreating the interwoven set of biochemical and mechanical cues in the cellular microenvironment, and the methods for implementing them. We emphasize applications that involve epithelial tissues for which 3D models could explain mechanisms of disease or aid in drug development.

Capturing complex 3D tissue physiology in vitro.

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

Epidermal growth factor receptor (EGFR) signaling in cancer

http://www.cellsignet.com/learn/papers/Jorissen.pdf

Epidermal growth factor receptor: mechanisms of activation and signalling.

Intracellular Trafficking of Epidermal Growth Factor Family Ligands Is Directly Influenced by the pH Sensitivity of the Receptor/Ligand Interaction

Successful use of growth factois in therapeutic and bioprocessig application requires overcoming two attenuation mechanisms: growth factor depletion and receptor down-regulation current ameliorative strategies use physiologically inappropriate high growth-factor concentrations, along with periodic media refeeding in vitro and reinjection or controlled-release devices in vivo We demonstrate a new approach derived from understanding how these attenuation mechanisms arise from ligand/receptor trafficking processes Specifically, a recombinant epidermal growth factor (EGF) mutant with reduced receptor binding affinity is a more potent migogenic stimulus of fibroblasts than natural EGF or transforming growth factor alpha because of its altered trafficking properties

Engineering epidermal growth factor for enhanced mitogenic potency

Cloning of authentic human epidermal growth factor as a bacterial secretory protein and its initial structure-function analysis by site-directed mutagenesis.

Salil K. Niyogi

Papers

Intracellular Trafficking of Epidermal Growth Factor Family Ligands Is Directly Influenced by the pH Sensitivity of the Receptor/Ligand Interaction

Engineering epidermal growth factor for enhanced mitogenic potency

Cloning of authentic human epidermal growth factor as a bacterial secretory protein and its initial structure-function analysis by site-directed mutagenesis.

Studies of the Ribonucleic Acid Polymerase from Escherichia coli

Nonessentiality of histidine 291 of Rhodospirillum rubrum ribulose-bisphosphate carboxylase/oxygenase as determined by site-directed mutagenesis.