Growth Factor Receptors And Signal Transduction
The biological effects of growth factors are mediated through specific receptors on target cells. Many receptors (e.g. erythropoietin (epo) receptor (R), GMCSF‐R) are from the haematopoietin receptor superfamily which dimerize after binding their ligand.
Dimerization of the receptor leads to activation of a complex series of intracellular signal transduction pathways, of which the three major ones are the JAK/STAT, the mitogen‐activated protein (MAP) kinase and the phosphatidylinositol 3 (PI3) kinase pathways (Fig. 1.7; see Fig. 15.2). The Janus‐associated kinase (JAK) proteins are a family of four tyrosine‐specific protein kinases that associate with the intracellular domains of the growth factor receptors (Fig. 1.7). A growth factor molecule binds simultaneously to the extracellular domains of two or three receptor molecules, resulting in their aggregation. Receptor aggregation induces activation of the JAKs which now phosphorylate members of the signal transducer and activator of transcription (STAT) family of transcription factors. This results in their dimerization and translocation from the cell cytoplasm across the nuclear membrane to the cell nucleus. Within the nucleus STAT dimers activate transcription of specific genes. A model for control of gene expression by a transcription factor is shown in Fig. 1.8. The clinical importance of this pathway is revealed by the finding of an activating mutation of the JAK2 gene as the cause of polycythaemia rubravera (see p. 166).
JAK can also activate the MAPK pathway, which is regulated by RAS and controls proliferation. PI3 kinases phophorylate inositol lipids which have a wide range of downstream effects including activation of AKT leading to block of apoptosis and other actions (Fig. 1.7; see Fig. 15.2). Different domains of the intracellular receptor protein may signal for the different processes (e.g. proliferation or suppression of apoptosis) mediated by growth factors.
A second smaller group of growth factors, including SCF, FLT‐3L and M‐CSF (Table 1.3), bind to receptors that have an extracellular immunoglobulin‐like domain linked via a transmembrane bridge to a cytoplasmic tyrosine kinase domain. Growth factor binding results in dimerization of these receptors and consequent activation of the tyrosine kinase domain. Phosphorylation of tyrosine residues in the receptor itself generates binding sites for signalling proteins which initiate complex cascades of biochemical events resulting in changes in gene expression, cell proliferation and prevention of apoptosis.