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Subclass I

EGF-R

Subclass II

Insulin-R

Subclass III

PDGF-R

I

II

I

II

Binding domain

Cys-rich domain

Binding domain

Cys-rich domain

NH 2

NH 2 NH 2

II

II II

α-unit

β-unit

α-unit

β-unit

NH 2

Immunoglobulin-like

repeat regions

Membrane

Insert domains–

contain an

autophosphorylation

site

COOH COOH COOH COOH

ATP, substrate and
autophosphorylation
binding sites

Transmembrane

domain

Fig. 17.11Diagrammatic representation of three receptor tyrosine kinase subclasses. The EGF subclass

contains two ligand-binding domains that are located in juxtaposition so that the ligands bind in a cleft

between the two domains. The two cysteine-rich domains are both located near the membrane surface.

On ligand binding, both the EGF and PDGF subclass receptors dimerise so that the intracellular tyrosine kinase

domains possess elevated activity and enhanced binding affinity relative to the monomeric forms. The

insulin subclass receptors are effectively dimeric, but, as with subclasses I and III, there is allosteric interaction

between the twoabhalves of each receptor on ligand binding. The tyrosine kinase domains of the three

subclasses show the greatest degree of homology between the three subclasses.

Example 3 RECEPTORS AND CANCER THERAPY

Cancers are caused by a mutation that stimulates a cell to grow in an uncontrolled

fashion. Inherited mutations cause a relatively small proportion of cancers;

approximately 10% of breast cancers, for example, are the result of inherited

mutations such as those caused by theBRCA1andBRAC2genes. A diversity of

spontaneous mutations underlie most cancers and a given type of cancer may be the

consequence of a range of mutations including single-letter changes to a codon,

gene deletions, insertions and duplications and chromosomal rearrangements. The

implication of this diversity of cause is that a given type of cancer such as breast

cancer may be the result of changes in different molecular pathways and hence will

need a range of drugs to be available to the clinician for the treatment of patients.

The implication of this is that for the effective treatment of a given patient it is vital

that the underlying cause is identified. Most current drug treatments target either a

membrane receptor or an enzyme. Examples of receptor targets are given below:

699 17.4 Mechanisms of signal transduction