Phosphoinositides as Signal Transducers

In previous sections, we have seen how signal transduction from cytokine receptors and receptor tyrosine kinases (RTKs) begins with formation of multiprotein complexes associated with the plasma membrane. Here we discuss how these receptors initiate signaling pathways that involve membrane-bound phosphorylated inositol lipids, collectively referred to as phosphoinositides. We begin with the branch of the phosphoinositide pathway that also is mediated by G protein-coupled receptors and then consider another branch that is not shared with these receptors.

Phospholipase Cy Is Activated by Some RTKs and Cytokine Receptors

As discussed in Chapter 13, hormonal stimulation of some G protein-coupled receptors leads to activation of the p isoform of phospholipase C (PLCp). This membrane-associated enzyme then cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to generate two important second messengers, 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Signaling via the IP3/DAG pathway leads to an increase in cytosolic Ca2+ and to activation of protein kinase C (see Figure 13-29).

Many RTKs and cytokine receptors also can initiate the IP3/DAG pathway by activating another isoform of phospholipase C, the y isoform (PLCy). The SH2 domains of PLCy bind to specific phosphotyrosines of the activated receptors, thus positioning the enzyme close to its membrane-bound substrate PIP2 (see Figure 13-28). In addition, the receptor kinase activity phosphorylates tyrosine residues on the bound PLCy, enhancing its hydrolase activity. Thus activated RTKs and cytokine receptors promote PLCy activity in two ways: by localizing the enzyme to the membrane and by phosphorylating it.

Recruitment of PI-3 Kinase to Hormone-Stimulated Receptors Leads to Activation of Protein Kinase B

In addition to initiating the IP3/DAG pathway, some activated RTKs and cytokine receptors can initiate another phosphoinositide pathway, the PI-3 kinase pathway, by re-

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