CANCER AND SIGNALLING IN NORMAL CELLS
A universal feature of the membranes that form the boundary of all cells is their capacity to permit the transfer of both chemical entities and information. Critical to the latter are trans-membrane receptors, of which the receptor tyrosine kinase family form a particularly important category in the context of regulating growth and proliferation. Through being able to respond to ligand binding by stimulating multiple pathways of intracellular proteins, activated receptors signal to the nucleus to regulate gene expression. Components of these pathways, including the receptors themselves, are frequently mutated in cancers, giving rise to aberrant proliferation control. To illustrate the principles of signalling we will consider one major example: the RAS-MAPK pathway activated by epidermal growth factor (EGF) through its receptor (EGFR), a member of the receptor tyrosine kinase family. The critical result of such signalling is the activation of transcription of key genes required for cells to enter the division cycle, a master regulator being MYC. Steroid hormones that diffuse across membranes before binding to their receptors also play significant roles in cancer and modulation of their effects has been an important therapeutic strategy.
A fundamental property of all cells is their capacity to respond to external signals. Mammalian cells receive a vast number of such signals in the form of chemical messengers, many of which are hormones – often called growth factors or mitogens (or cytokines if they’ve been secreted by cells of the immune system). The intracellular pathways that are activated are complex and their upshot is a pattern of gene expression that determines the critical decisions that cells have to take – whether to proliferate or remain quiescent, to change their function (differentiate) or even to commit suicide. However, only four basic mechanisms are used to transduce these signals. Three of these utilise proteins that span the plasma membrane (Fig. 1). These cell proteins comprise: enzyme-coupled receptors, G-protein-coupled receptors (GPCRs) and ligand-gated ion channel receptors. The fourth system uses receptors within the cell to respond to steroid hormones.
1.Representation of the structures of trans-membrane signalling receptors.
We shall consider each of these four, in turn, focusing on their actions in normal cells. The greatest emphasis will be on enzyme-coupled receptors because they play the major role in regulating proliferation and both, themselves, and components of the intracellular signal pathways they drive frequently behave aberrantly in cancer.
Each of these signal systems differs in mechanism but they are really just a variant on the theme of transmitting information carried by a chemical signal to the cell so that it adjusts its lifestyle accordingly. The four key features of cellular signalling are (1) specificity conferred by ligand–protein and protein-protein interactions; (2) signal amplification generated when activated enzymes are components of pathways; (3) the capacity for pathway convergence (two signals affect the same messenger) and/or divergence (multiple pathways emanate from a single component); and (4) signal termination (by decrease in the concentration of the activating ligand together with dephosphorylation and/or receptor internalisation).