Signalling Pathways Operated by Receptor Protein Tyrosine Kinases

growth, and osmoregulation. MAP kinase is a regulator of embryonic development and the immune response in Drosophila . It acts as a regulator in slime moulds, plants, and fungi.

The Ca2 –calmodulin pathway

The elevation of cytosol Ca2 following activation of PLC results in widespread protein phosphorylation by serine/threonine kinases. These include the broad spectrum Ca2 -calmodulin-dependent protein kinase II (CaM-kinase II) (see page 228), myosin light chain kinase (MLCK), phosphorylase kinase, and EF-2 kinase. All of these are activated by Ca2 –calmodulin.

The level of phosphorylation of a particular substrate at any time must be determined by the rates of both phosphorylation and dephosphorylation. Ca2 –calmodulin can affect this balance through activation of the protein phosphatase calcineurin. This leads to the activation of transcription factors that play essential roles in the activation of T lymphocytes (Chapter 17). Clearly, Ca2 is an extremely versatile second messenger modulating numerous intracellular signals.

Activation of PI 3-kinase

Association of the p85 adaptor subunit of PI 3-kinase with the tyrosinephosphorylated receptor positions the attached p110 catalytic subunit at the membrane where it phosphorylates inositol phospholipids at the 3 position of the inositol ring. The p110 subunit can also be activated directly by Ras. This results in activation of PKB, of prime importance in cell survival, proliferation, motility, and glucose metabolism. This pathway is considered in Chapter 18.

Direct phosphorylation of STAT transcription factors

The simplest way by which plasma membrane receptors alter gene expression is through the direct phosphorylation of transcription factors. The action of the interferons is an example. The STATs are targets of interferon receptors and they also mediate EGF and PDGF signalling.184,185 STAT1a (p91) and STAT1b (p84) possess SH2 domains that enable them to associate with the phosphotyrosines of activated receptors (Figure 12.23). They themselves are then phosphorylated on tyrosine residues, causing them to form dimers

that translocate to the nucleus where they promote transcription of early response genes such as c-fos (see page 525). The STAT dimer formed after phosphorylation by the PDGF receptor was originally described as Sisinducible factor (SIF), because it was observed in cells exposed to the viral oncogene product v-Sis. This is closely related to PDGF and activates the same signal transduction pathway.186,187

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