on each monomer forming SH2 or phosphotyrosine binding (PTB) domains that serve
as docking sites for effector proteins that possess SH2 sites causing the phosphoryl-
ation and activation of the effector. One such effector protein for the insulin receptor
is insulin receptor substrate-1 (IRS). Effector proteins that bind either possess enzyme
activity such as kinase, phosphatase, lipase and GTPase or act as adaptors that act to
link the activated and phosphorylated receptor with other effectors. In addition, the
effector may possess other binding domains to which further effectors can bind. This
multiplicity of binding domains and bound effectors enable a web of signalling
pathways and cascades to be established with the potential for transduction pathway
branching to meet prevailing cellular demands.Receptor serine and threonine kinases
Complementary to the tyrosine kinase group of receptors is a second group of protein
kinase receptors characterised by their ability to autophosphorylate serine and
threonine residues in the intracellular domain of the receptor. These protein serine/
threonine kinase receptors are specific for members of the transforming growth factor
(TGF)-bsuperfamily of receptors which regulate growth, differentiation, migration
and cell adhesion. They are classified into a number of subgroups on the basis of their
structure, particularly their serine/threonine kinase domain. They are all single trans-
membrane receptors that on ligand binding form hetero-oligomeric complexes
between subgroup types. This stimulates autophosphorylation and activation of the
serine/threonine kinase activity towards other cytosolic proteins that are components
of the transduction pathway.
Like the G-protein-coupled receptors, receptor protein kinases stimulate numerous
transduction pathways. The downstream members of these transduction pathways
include the phospholipases and phosphoinositide kinases that are also involved in the
G-protein transduction pathways. Receptor protein kinases in turn are subject to
regulation by ubiquitin ligases, protein kinases and phosphatases and various adaptor
proteins. Importantly, 30% of all RTKs are repeatedly found either mutated or
overexpressed in a wide range of different human malignancies. EGFR, for example,
is associated with breast cancers. One of a number of effectors unique to the receptor
protein kinases is Ras, a membrane-bound guanosine binding protein with intrinsic
GTPase activity, involved in cell growth and development in all eukaryotes. Activated
Ras triggers the mitogen-activated protein kinase (MAP kinase cascade) which in turn
phosphorylates multiple proteins in the nucleus including transcription factors that
regulate gene expression in cell division, cell adhesion, apoptosis and cell migration.
The Ras gene was the first oncogene to be discovered to be associated with a human
cancer. It is the target for the treatment of various forms of cancer by the development
of monoclonal antibodies.Cytokine receptors
A group of receptors closely related to the protein kinase receptors are thecytokine
receptors. Cytokines are a group of peptides and proteins intimately involved in
cell signalling. They play key roles in the immune system and are involved in701 17.4 Mechanisms of signal transduction