Kinase, cellular

CD7 transmembrane protein linked to PI-3 (phosphoinositol-3) kinase cellular function not thoroughly clarified... 

Phosphatase tensin on chromosome ten mutated in multiple advanced cancers Phosphatidyl inositol kinase cellular homolog AKT 8 mouse thymic retroviral oncogene PDZ postsynaptic density protein drosophila disc large tumor suppressor ZO zonula occludens... 

L.A. de la Rosa, A. Alfonso, N. Vilarino, M.R. Vieytes, T. Yasumoto, and L.M. Botana, Maitotoxin-induced calcium entry in human lymphocytes—Modulation by yessotoxin, Ca " channel blockers and kinases. Cellular Signaling 13 (2001) 711-716. 

The last part of this account will be devoted to protein kinases and protein phosphatases and some recent results we have obtained for them. Protein kinases and phosphatases are signaling biomolecules that control the level of phosphorylation and dephosphorylation of tyrosine, serine or threonine residues in other proteins, and by this means regulate a variety of fundamental cellular processes including cell growth and proliferation, cell cycle and cytoskeletal integrity. 

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

BVdU differs from IdU and F TdU by being specifically phosphorylated in the 5 -position by herpes simplex vims type-1 (HSV-1) induced thymidine kinase. This restricts its action to cells infected by HSV-1. It is less active against genital herpes (HSV-2). HSV-l-induced thymidine kinase converts BVdU to the corresponding 5 -mono- and diphosphate, but HSV-2-induced thymidine kinase stops at the stage of the 5 -phosphate of BVdU. Apparendy, cellular kinases phosphorylate BVdU-5 -diphosphate to the corresponding 5 -triphosphate, which inhibits HSV-1 DNA polymerase to a greater extent than similar cellular DNA polymerases. 

FIAC also strongly inhibits HCMV and Epstein-Barr vims (EBV) in vitro the two vimses known not to induce a specific viral thymidine kinase for their repHcation. However, HCMV may stimulate cellular kinases that can anabolize FIAC to its 5 -triphosphate, which specifically inhibits the HCMV-encoded DNA polymerase. This selective activity suggests that FIAC should be evaluated against HCMV infections. FIAC-ttiphosphate incorporated into DNA has shown strong in vitro activity against the DNA polymerases of human hepatitis B vims (HBV) and of woodchuck hepatitis vims (WHV) (37). 

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341 -17-1], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes vimses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. 

C-terminal tail (Tyr 527 in c-Src). Phosphorylation of Tyr 419 activates the kinase phosphorylation of Tyr 527 inhibits it. Crystal structures of a fragment containing the last four domains of two members of this family were reported simultaneously in 1997—cellular Src by the group of Stephen Harrison and Hck by the group of John Kuriyan. The two structures are very similar, as expected since the 440 residue polypeptide chains have 60% sequence identity. The crucial C-proximal tyrosine that inhibits the activity of the kinases was phosphorylated in both cases the activation loop was not. 

The abundance of many protein kinases in cells is an indication of the great importance of protein phosphorylation in cellular regulation. Exactly 113 protein kinase genes have been recognized in yeast, and it is estimated that the human genome encodes more than 1000 different protein kinases. Tyrosine kinases (protein kinases that phosphorylate Tyr residues) occur only in multicellular organisms (yeast has no tyrosine kinases). Tyrosine kinases are components of signaling pathways involved in cell-cell communication (see Chapter 34). 

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

Let us consider Figure 5.3 again. Both pyruvate kinase and dtrate synthase (enzymes III and V) are inhibited by elevated ATP concentrations. During citric acid production ATP concentrations are likely to arise (ATP produced in glycolysis) and either of these enzymes could, if inhibited, slow down the process. In fact all of the evidence suggests that both enzymes are modified or controlled in some way such that they are insensitive to other cellular metabolites during citric add production. 

AKAPs are a diverse family of about 75 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins to cellular compartments and thereby limit and integrate cellular signalling processes at specific sites. This compartmentalization of signalling by AKAPs contributes to the specificity of a cellular response to a given external stimulus (e.g. a particular hormone or neurotransmitter). 

MAP kinase signaling promotes differentiation ofPC12 cells. Adaptor proteins are able to regulate the time course of signaling events, and therefore the cellular outcome. 

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