Signal transduction cAMP-dependent protein kinase activation

Protein kinases are central to many signal-transduction pathways. Protein kinases are central to all three signal-transduction pathways described in this chapter. In the epinephrine-initiated pathway, cAMP-dependent protein kinase (PKA) lies at the end of the pathway, transducing information represented by an increase in cAMP concentration into covalent modifications that alter the activity of key metabolic enzymes. In the insulin- and EGF-initiated pathways, the receptors themselves are protein kinases and several additional protein kinases participate downstream in the pathways. Signal amplification due to protein kinase cascades are common features of each of these pathways and many others. Furthermore, protein kinases often phosphorylate multiple substrates, including many not considered herein, and by this means are able to generate a diversity of responses. 

When the receptor is unoccupied, the Gs protein (X, subunit has GDP bound and is complexed with the ft,y-dimer. The binding of hormone (1) activates the receptor and leads to replacement of GDP with GTP (2). The activated subunit interacts with and activates adenylate cyclase. (3) The cAMP produced binds to cAMP-dependent protein kinase. Signal transduction ends when the ligand leaves the... 

Ras-pathway signal transduction [11,33,67,68]. Selective activation of cAMP-dependent protein kinase type I (cAKI), but not type II, is sufficient to mediate an inhibition of T cell replication induced through the TCR/CD3 complex [55]. It may be essential for a reverse reaction preventing excessive cell activation. 

By comparison with alcohol asymmetric acylation (i.e., esterification) as discussed above, alcohol asymmetric phosphorylation has not attracted so much attention from the synthetic community thus far. This is rather curious given the pivotal importance of phosphorylated alcohols in biological systems where three of the most important and weU-studied signal transduction pathways, the mitogen-activated protein kinase pathway (MAPK), adenylyl cyclase dependent pathway (cAMP), and inositol triphosphate/diacylglycerol pathway (IP3/DAG), all rely critically on chemo- and/or stereoselective alcohol phosphorylation/dephosphorylation by kinase/phosphatase enzymes, respectively [76]. 

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