R4.2: Signal Transduction

Signal transduction refers to the detection of a ‘signal’ at one point in the cell and the downstream pathway that allows the cell to respond to that signal. For instance, a growth factor may bind to a cell membrane receptor, which then causes activation of a pathway that eventually leads to altered gene expression in the nucleus. Signal transduction proteins are usually anchored to the cell membrane where they are able to interact with transmembrane proteins.

Example: RAS Signal Transduction

The human genome contains three RAS genes – KRAS, HRAS, and NRAS – which have all been implicated as proto-oncogenes. RAS is a membrane-bound protein which faces the cytoplasm. It normally switches between an active and inactive state, governed by the binding of GTP (active) or GDP (inactive) to a target site. When a neighbouring transmembrane receptor is activated (eg ERBB2), RAS switches to the active mode by replacement of GDP with GTP. It is then able to start a cascade of protein phosphorylation that lead to cell proliferation (the MAPK pathway). The first protein in this cascade is RAF of which there are also multiple variants.
A mutation in any of the RAS genes may lead to dysfunctional protein. The protein may be kept in a permanent ‘on’ state, leading to self sufficiency in growth signals. Loss of RAS leads to problems with cellular response to growth factors. RAS is mutated in 15-20% of all tumours.
In addition to mutation of RAS, the downstream members of the MAPK pathway can also be mutated leading to permanent activation of cell proliferation signalling.