%0 Journal Article
%T Tyrosine kinase signalling in breast cancer: Epidermal growth factor receptor - convergence point for signal integration and diversification
%A Norbert Prenzel
%A Esther Zwick
%A Michael Leserer
%A Axel Ullrich
%J Breast Cancer Research
%D 2000
%I BioMed Central
%R 10.1186/bcr52
%X In complex organisms individual cells communicate through a variety of molecular messengers and actions, such as growth factors, hormones, cytokines, neuropeptides or cell-cell contact, which are recognized by diverse signal-generating cell-surface receptors and thereby regulate cellular growth, differentiation and survival. One important membrane-spanning protein that integrates the information flux from multiple sources is the EGFR, which was the first mammalian signalling protein to be fully characterized [1]. The EGFR belongs to a family of four closely related receptor tyrosine kinases (RTKs): EGFR/ErbB1, HER2/ErbB2/neu, HER3/ErbB3 and HER4/ErbB4. These RTKs are able to form homodimers or heterodimers, and regulate a large diversity of biological processes [2,3]. Deregulation of this tightly controlled signalling network by receptor overexpression, autocrine ligand stimulation or activating mutations has been frequently implicated in several types of human cancers, especially of the breast, ovary, lung and prostate [4,5].Generally, ligands for the EGFR such as EGF, transforming growth factor-¦Á or heparin-binding EGF-like growth factor (HB-EGF) are synthesized as transmembrane precursors and are proteolytically cleaved by metalloproteinases to yield the mature growth factor, which subsequently activates receptors on the same or on adjacent cells [6]. Following ligand binding, the EGFR dimerizes and becomes tyrosine phosphorylated on distinct residues by the intrinsic kinase activity of the receptor [7]. These residues represent docking sites for first stage signal transducers with enzymatic activity, such as phospholipase C¦Ã, and adapter proteins, such as Shc, Grb2 and Nck, which couple receptor activation to downstream pathways, calcium metabolism, and protein kinase C (PKC) signalling, transcription and phospholipid turnover. Apart from these established functions, the EGFR has been found to be a critical down-stream element of signalling systems, including th
%K cytokines
%K epidermal growth factor receptor
%K G-protein-coupled receptors
%K integrins
%K metalloproteinases
%K Ras-mitogen-activated protein kinase
%K transactivation
%U http://breast-cancer-research.com/content/2/3/184