CANCER AND DIFFERENT TYPES OF RECEPTORS
In mammals there are four types of enzyme-coupled receptors that have intrinsic enzymatic activity within a single trans-membrane protein: those in which the enzyme phosphorylates the amino acid tyrosine (receptor tyrosine kinases or RTKs (Fig. 1), receptor serine/threonine kinases, receptor guanylyl cyclases and receptor-like tyrosine phosphatases.
In a smaller group of enzyme- coupled receptors the cytosolic domain does not have intrinsic enzyme activity but instead recruits and activates cytoplasmic tyrosine kinases to relay the signal. There is also a family of histidine-specific protein kinases present mainly in bacteria.
The RTKs are the largest class of enzyme-coupled receptors and we will focus on them because of the major roles they play in controlling cell proliferation and the fact that they frequently signal abnormally in cancer (Fig. 2).
2. Tyrosine kinase receptor activation involves trans-phosphorylation.
In the case of signals that bind to cell surface receptors, binding of the hormone/growth factor to the extracellular part of the receptor promotes a conformational change that is transmitted to the intracellular domain, via the trans-membrane bridge. This is often facilitated by the capacity to bind to two receptors at once (so-called ‘cross-linking’), which, in effect, draws the two receptors together.
The intracellular domains of these receptors are kinase enzymes that can add phosphate groups to specific target proteins, including the receptor’s own intracellular domains (Fig. 3).
3.The epidermal growth factor receptor, EGFR.
Hormone binding to the ectodomains juxtaposes the cytosolic domains of two receptors, promoting a conformational change that results in catalytic activation. Activated receptors phosphorylate other receptors of the same type (trans-phosphorylation), rather than tyrosine residues within the same molecule but the critical point is that a set of phosphorylated tyrosine residues are created to act as docking sites for intracellular signalling proteins (Fig. 4).
4.EGFR family receptors (EGFR, ERBB2, ERBB3 and ERBB4) and ligands.
The hormone, epidermal growth factor (EGF), is one of the first growth hormones to be identified. Its name reflecting the fact that it stimulates the growth of epidermal (skin) cells in animals. Epidermal growth factor differs from most other RTK ligands in being monomeric. It, therefore, binds to EGFR with a 1:1 stoichiometry but the conformational change induced in the ectodomain promotes receptor dimerisation with the two tyrosine kinase domains taking up an asymmetrical structure stabilised by the juxtamembrane region of the receptor. There are four members of the EGFR family (Fig. 4) to which a variety of ligands, in addition to EGF, can bind with differing affinity, the exception being ERBB2, which has no direct ligand, forms signalling heterodimers with the other members of the family.