First messengers protein phosphorylation

The details of the mechanism by which CREB influences gene expression are becoming increasingly understood (Fig. 23-9) [62, 63]. In the basal, or unstimulated, state, CREB is bound to its CREs but does not alter transcriptional rates under most circumstances. Stimulation of a cell by a variety of first messengers leads to the phosphorylation and activation of CREB, which then leads to the regulation of gene transcription. Such phosphorylation of CREB occurs on a single serine residue, serine 133, and can be mediated by one of several protein kinases. 

The detailed mechanisms involved in CREB phosphorylation were first established for the cAMP pathway. A first messenger that increases cAMP concentrations leads to activation of PKA and to translocation of the free catalytic subunit of the protein kinase into the nucleus, where it phosphorylates CREB on serine 133. Such phosphorylation then promotes the binding of CREB to a CREB-binding protein (CBP). CBP, upon binding CREB, interacts directly with the RNA polymerase II complex, which mediates the initiation of transcription. In most cases, such interactions lead to the activation of transcription, although it is possible that the expression of some genes may be repressed. 

The substrates of the MAP kinase pathway are very diverse and include both cytosolic and nuclear localized proteins. Phospholipase A2 and transcription factors of the Ets family are well characterized substrates of the ERK pathway. Phosphorylation of a Ser residue of phospholipase A2 by ERK proteins leads to activation of the lipase activity. Consequently, there is an increase in release of arachidonic acid and of lyso-phospholipids, which can act immediately as diffusible signal molecules or may represent first stages in the formation of second messenger molecules. 

First, the binding of one hormone molecule to one receptor catalytically activates several Gs molecules. Next, by activating a molecule of adenylyl cyclase, each active Gsa molecule stimulates the catalytic synthesis of many molecules of cAMP. The second messenger cAMP now activates PKA, each molecule of which catalyzes the phosphorylation of many molecules of the target protein—phosphorylase b kinase in Figure 12-16. This... 

The substrates for neurotrophin Trk receptors-phos-pholipase C-y, PI3-K SHC and Grb2 adaptor proteins-are utilized by many tyrosine kinase receptors. This raises the question of how these phosphorylation events lead to different biological outcomes (Chao, 1992b). There are several possibilities. First, the strength and duration of the receptor autophosphorylation events may determine downstream signalling outcomes. Second, differential signalling may be controlled by specific dephosphorylation events. Third, there may be unique second messengers or substrates which determine the specific nature of the response. 

PLCy is a member of PLC family proteins (other members are PLC(5, PLC5, PLCs, PLCi etc.) that hydrolyzes phosphatidylinositol 4,5-bisphosphate into DG and IP3, both of which are second messenger to promote PKC activation and intracellular Ca mobilization, respectively (Rhee 2001). PLCy is the first example of non-tyrosine kinase protein, whose structure contains SH2 and SH3 domains (Stahl et al. 1988). PLCy is also unique in its regulatory mechanism, where tyrosine phosphorylation of the protein can up-regulate the enzyme activity. Under this background, fxmction of PLCy in oocyte maturation and fertilization has been analyzed extensively in relation to tyrosine kinase signaling. In fact, tyrosine kinase-dependent activation of PLCy at fertilization has been demonstrated in some... 

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