immunological, inflammatory and infectious diseases. They have also been termed
lymphokines, interleukins and chemokines. They act by binding to specific cytokine
receptors that structurally resemble protein kinase receptors in that they exist as
functional homo- or hetero-oligomers but they lack intrinsic kinase activity. Binding
of the cytokine activates the receptor enabling it to recruit a non-receptor tyrosine
kinase, such as a member of the src family or the Janus kinases family, to the
cytoplasmic side of the receptor. Activation of this kinase by the receptor enables
the receptor–kinase complex to recruit other effector proteins that trigger a signalling
cascade linked to the up- or downregulation of genes and their transcription factors.Protein tyrosine phosphatases
Crucial to the control of cell signalling involving receptor kinases is the existence of a
group of protein tyrosine and serine/threonine phosphatases that can either deactivate
or activate pathways by dephosphorylation of receptors or effectors. The human
genome includes approximately 100 genes for tyrosine phosphatases. This is a similar
number of genes as for RTKs suggesting that the two families are partners in the
regulation of the signalling response with the kinases controlling the amplitude of the
responses and the phosphatases their rate and duration. Some of the phosphatases
are purely cytoplasmic whilst others are receptor-like and are referred to asreceptor
tyrosine phosphatases(RTPs). Most protein tyrosine phosphatases have two phos-
phatase domains for reasons that are not clear but their specificity may be linked
to interaction between the two sites. The activity of the phosphatases appears to be
linked to their own phosphorylation and a significant number have a SH2 domain
similar to that of the receptor tyrosine kinases. There is currently great interest in
protein tyrosine phosphatases as many have been shown to act a tumour suppressors
in contrast to protein tyrosine kinases some of which act as oncoproteins.17.4.5 Dynamics of signalling pathways
The classical view of receptor signal transduction is that the process is alinear
cascade:agonist!receptor!effectorðsÞ!transduction!response
However, the current evidence is that such linear cascades are an oversimplification
of the actual organisation. Most receptors appear to operate in complex and highly
integratednetworksthat control several linked processes. GPCRs and PTKs that
control many physiologically important pathways commonly merge to form inte-
grated networks. Receptors in such networks share key components ornodesthat
mediate and modify the receptors’ signals and which are the sites of crosstalk between
the receptors that can result in signal divergence. Crosstalk between GPCRs and RTKs
is common and may be bidirectional in that the GPCR may be ‘upstream’ or ‘down-
stream’ of the RTK signal transduction. This has given rise to the concept oftrans-
activationby which a given receptor is activated by a ligand of a heterologous
receptor that may belong to a different class of receptor with respect to the signal
transduction mechanism. Thus an activated RTK may initiate GPCR signalling by causing702 Cell membrane receptors and cell signalling