Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Salivary secretions contain phosphoproteins that contain phosphorylation sites composed of serine residues in acidic environments. The hypothesis of this study is that a protein kinase responsible for phosphorylating these proteins is similar to kinases that phosphorylate proteins in other glandular secretions. Homogenates and subfractions from macaque parotid glands were able to phosphorylate synthetic peptide substrates containing each of the phosphorylation sites in acidic proline-rich proteins, statherin, and histatin 1. Activity was purified from Golgi membranes to greater than 220-fold by extraction with Triton X-100 and affinity chromatography with the use of immobilized ATP. The enzyme preferred substrates containing serine residues in a specific acidic environment, particularly those containing the Ser-Xaa-acidic sequence, preferred ATP over GTP, and was sensitive to high concentrations of heparin. These characteristics are similar to those reported for Golgi casein kinase, which phosphorylates casein in vivo. Based on these observations, the parotid gland kinase may be related to other Golgi-localized serine kinases.
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PMID:Purification of kinase activity from primate parotid glands. 1170 47

Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-kappa B activation. In a yeast two-hybrid screening for potential RIP-interacting proteins, we identified ZIN (zinc finger protein inhibiting NF-kappa B), a novel protein that specifically interacts with RIP. ZIN contains four RING-like zinc finger domains at the middle and a proline-rich domain at the C terminus. Overexpression of ZIN inhibits RIP-, IKK beta-, TNF-, and IL1-induced NF-kappa B activation in a dose-dependent manner in 293 cells. Domain mapping experiments indicate that the RING-like zinc finger domains of ZIN are required for its interaction with RIP and inhibition of RIP-mediated NF-kappa B activation. Overexpression of ZIN also potentiates RIP- and TNF-induced apoptosis. Moreover, immunofluorescent staining indicates that ZIN is a cytoplasmic protein and that it colocalizes with RIP. Our findings suggest that ZIN is an inhibitor of TNF- and IL1-induced NF-kappa B activation pathways.
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PMID:A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation. 1185 71

Sorbitol, "osmotic stress", stimulates GLUT4 glucose transporter translocation to the plasma membrane and glucose transport by a phosphatidylinositol (PI) 3-kinase-independent mechanism that reportedly involves non-receptor proline-rich tyrosine kinase-2 (PYK2) but subsequent events are obscure. In the present study, we found that extracellular signal-regulated kinase (ERK) pathway components, growth-factor-receptor-bound-2 protein, son of sevenless (SOS), RAS, RAF and mitogen-activated protein (MAP) kinase/ERK kinase, MEK(-1), operating downstream of PYK2, were required for sorbitol-stimulated GLUT4 translocation/glucose transport in rat adipocytes, L6 myotubes and 3T3/L1 adipocytes. Furthermore, sorbitol activated atypical protein kinase C (aPKC) through a similar mechanism depending on the PYK2/ERK pathway, independent of PI 3-kinase and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Like PYK2/ERK pathway components, aPKCs were required for sorbitol-stimulated GLUT4 translocation/glucose transport. Interestingly, sorbitol stimulated increases in phospholipase D (PLD) activity and generation of phosphatidic acid (PA), which directly activated aPKCs. As with aPKCs and glucose transport, sorbitol-stimulated PLD activity was dependent on the ERK pathway. Moreover, PLD-generated PA was required for sorbitol-induced activation of aPKCs and GLUT4 translocation/glucose transport. Our findings suggest that sorbitol sequentially activates PYK2, the ERK pathway and PLD, thereby increasing PA, which activates aPKCs and GLUT4 translocation. This mechanism contrasts with that of insulin, which primarily uses PI 3-kinase, D3-PO(4) polyphosphoinositides and PDK-1 to activate aPKCs.
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PMID:Sorbitol activates atypical protein kinase C and GLUT4 glucose transporter translocation/glucose transport through proline-rich tyrosine kinase-2, the extracellular signal-regulated kinase pathway and phospholipase D. 1187 94

In vascular smooth muscle (VSM) and many other cells, G protein receptor-coupled activation of mitogen-activated protein kinases has been linked, in part, to increases in free intracellular Ca(2+). Previously, we demonstrated that ionomycin-, angiotensin II-, and thrombin-induced activation of extracellular signal-regulated kinase (ERK)1/2 in VSM cells was attenuated by pretreatment with KN-93, a selective inhibitor of the multifunctional Ca(2+)/calmodulin-dependent protein kinase (CaM kinase II). In the present study, we show that the Ca(2+)-dependent pathway leading to activation of ERK1/2 is preceded by nonreceptor proline-rich tyrosine kinase (PYK2) activation and epidermal growth factor (EGF) receptor tyrosine phosphorylation and is attenuated by inhibitors of src family kinases or the EGF receptor tyrosine kinase. Furthermore, we demonstrate that pretreatment with KN-93 or a CaM kinase II inhibitor peptide inhibits Ca(2+)-dependent PYK2 activation and EGF receptor tyrosine phosphorylation in response to ionomycin, ATP, and platelet-derived growth factor but has no effect on phorbol 12,13-dibutyrate- or EGF-induced responses. The results implicate CaM kinase II as an intermediate in the Ca(2+)/calmodulin-dependent activation of PYK2.
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PMID:CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle. 1188 Feb 63

PAK1 is a protein kinase downstream of the small GTPases Rac and Cdc42 that previous work has implicated in endothelial cell migration via modulation of cell contraction. The first proline-rich region of PAK that binds to an SH3 domain from the adapter protein NCK was responsible for these dominant-negative effects. To test the role of PAK in angiogenesis, we prepared a peptide in which the proline-rich region was fused to the polybasic sequence from the HIV Tat protein to facilitate entry into cells. We show that the short peptide selectively binds NCK, whereas a mutant peptide does not. Treatment of cells with the PAK peptide but not the control peptide disrupts localization of PAK. This peptide specifically inhibited endothelial cell migration and contractility similarly to full-length dominant-negative PAK. In an in vitro tube-forming assay, the PAK peptide specifically blocked formation of multicellular networks. In an in vivo chick chorioallantoic membrane assay, the PAK peptide specifically blocked angiogenesis. These results, therefore, suggest a role for PAK in angiogenesis.
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PMID:A dominant-negative p65 PAK peptide inhibits angiogenesis. 1193 38

Exercise increases glucose transport in muscle by activating 5'-AMP-activated protein kinase (AMPK), but subsequent events are unclear. Presently, we examined the possibility that AMPK increases glucose transport through atypical protein kinase Cs (aPKCs) by activating proline-rich tyrosine kinase-2 (PYK2), ERK pathway components, and phospholipase D (PLD). In mice, treadmill exercise rapidly activated ERK and aPKCs in mouse vastus lateralis muscles. In rat extensor digitorum longus (EDL) muscles, (a) AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-d-riboside (AICAR), activated PYK2, ERK and aPKCs; (b) effects of AICAR on ERK and aPKCs were blocked by tyrosine kinase inhibitor, genistein, and MEK1 inhibitor, PD98059; and (c) effects of AICAR on aPKCs and 2-deoxyglucose (2-DOG) uptake were inhibited by genistein, PD98059, and PLD-inhibitor, 1-butanol. Similarly, in L6 myotubes, (a) AICAR activated PYK2, ERK, PLD, and aPKCs; (b) effects of AICAR on ERK were inhibited by genistein, PD98059, and expression of dominant-negative PYK2; (c) effects of AICAR on PLD were inhibited by MEK1 inhibitor UO126; (d) effects of AICAR on aPKCs were inhibited by genistein, PD98059, 1-butanol, and expression of dominant-negative forms of PYK2, GRB2, SOS, RAS, RAF, and ERK; and (e) effects of AICAR on 2DOG uptake/GLUT4 translocation were inhibited by genistein, PD98059, UO126, 1-butanol, cell-permeable myristoylated PKC-zeta pseudosubstrate, and expression of kinase-inactive RAF, ERK, and PKC-zeta. AMPK activator dinitrophenol had effects on ERK, aPKCs, and 2-DOG uptake similar to those of AICAR. Our findings suggest that effects of exercise on glucose transport that are dependent on AMPK are mediated via PYK2, the ERK pathway, PLD, and aPKCs.
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PMID:Activation of the ERK pathway and atypical protein kinase C isoforms in exercise- and aminoimidazole-4-carboxamide-1-beta-D-riboside (AICAR)-stimulated glucose transport. 1197 88

Hepatitis C virus (HCV) sets up a persistent infection in patients that likely involves a complex virus-host interaction. We previously found that the HCV nonstructural 5A (NS5A) protein interacts with growth factor receptor-binding protein 2 (Grb2) adaptor protein and inhibits the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by epidermal growth factor (EGF). In the present study, we extended this analysis and investigated the specificity of the Grb2-NS5A interaction and whether the subversion of mitogenic signaling involves additional pathways. NS5A containing mutations within the C-terminal proline-rich motif neither bound Grb2 nor inhibited ERK1/2 activation by EGF, demonstrating that NS5A-Grb2 binding and downstream effects were due to direct interactions. Interestingly, NS5A could also form a complex with the Grb2-associated binder 1 (Gab1) protein in an EGF treatment-dependent manner. However, the NS5A-Gab1 association, which appeared indirect, was not mediated by direct NS5A-Grb2 interaction but was likely dependent on direct NS5A interaction with the p85 subunit of phosphatidylinositol 3-kinase (PI3K). The in vivo association of NS5A with p85 PI3K required the N-terminal, but not the C-terminal, region of NS5A. The downstream effects of the NS5A-p85 PI3K interaction included increased tyrosine phosphorylation of p85 PI3K in response to EGF. Consistent with this observation and the antiapoptotic properties of NS5A, we also detected enhanced tyrosine phosphorylation of the downstream AKT protein kinase and increased serine phosphorylation of BAD, a proapoptotic factor and an AKT substrate, in the presence of NS5A. These results collectively suggest a model in which NS5A interacts with Grb2 to inhibit mitogenic signaling while simultaneously promoting the PI3K-AKT cell survival pathway by interaction with p85 PI3K, which may represent a crucial step in HCV persistence and pathogenesis.
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PMID:Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase. 1218 4

Human papillomavirus type 16 (HPV16) is the most common cause of cervical carcinoma. Cervical cancer develops from low-grade lesions that support the productive stages of the virus life cycle. The 16E1 wedge E4 protein is abundantly expressed in such lesions and can be detected in cells supporting vegetative viral genome amplification. Using an inducible mammalian expression system, we have shown that 16E1 wedge E4 arrests HeLa cervical epithelial cells in G(2). 16E1 wedge E4 also caused a G(2) arrest in SiHa, Saos-2 and Saccharomyces pombe cells and, as with HeLa cells, was found in the cytoplasm. However, whereas 16E1 wedge E4 is found on the keratin networks in HeLa and SiHa cells, in Saos-2 and S. pombe cells that lack keratins, 16E1 wedge E4 had a punctate distribution. Mutagenesis studies revealed a proline-rich region between amino acids 17 and 45 of 16E1 wedge E4 to be important for arrest. This region, which we have termed the "arrest domain," contains a putative nuclear localization signal, a cyclin-binding motif, and a single cyclin-dependent kinase (Cdk) phosphorylation site. A single point mutation in the putative Cdk phosphorylation site (T23A) abolished 16E1 wedge E4-mediated G(2) arrest. Arrest did not involve proteins regulating the phosphorylation state of Cdc2 and does not appear to involve the activation of the DNA damage or incomplete replication checkpoint. G(2) arrest was also mediated by the E1 wedge E4 protein of HPV11, a low-risk mucosal HPV type that also causes cervical lesions. The E1 wedge E4 protein of HPV1, which is more distantly related to that of HPV16, did not cause G(2) arrest. We conclude that, like other papillomavirus proteins, 16E1 wedge E4 affects cell cycle progression and that it targets a conserved component of the cell cycle machinery.
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PMID:Identification of a G(2) arrest domain in the E1 wedge E4 protein of human papillomavirus type 16. 1220 59

Modulation of voltage-gated potassium (Kv) channels by protein phosphorylation plays an essential role in the regulation of the membrane properties of cells. Protein-protein binding domains, such as Src homology 3 (SH3) domains, direct ion channel modulation by coupling the channels with intracellular signaling enzymes. The conventional view is that protein kinase binding to ion channels leads to modulation by bringing the channel substrate into physical proximity to the enzyme, thereby fostering covalent modification of the channel. The SH3 domain binding-dependent functional suppression of Kv1.5 currents by Src family protein tyrosine kinases (PTKs) is considered a canonical example of this type of mechanism. In the present study we address whether the SH3-dependent binding of Src family PTKs to Shaker family Kvs mediates modulatory events that are independent of and/or dependent on Src-catalyzed tyrosine phosphorylation of the channel. We find that Src binding and tyrosine phosphorylation are each able to modulate Kv1 family macroscopic channel currents independently. SH3-dependent binding of Src leads to the suppression of both Kv1.5 and Kv1.4 (modified to contain proline-rich SH3 domain binding sites) macroscopic currents even in the absence of Src-catalyzed tyrosine phosphorylation, whereas binding-independent tyrosine phosphorylation by Src leads to the suppression of Kv1.5 macroscopic currents and the modulation of Kv1.4 inactivation kinetics.
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PMID:Phosphorylation-dependent and phosphorylation-independent modes of modulation of shaker family voltage-gated potassium channels by SRC family protein tyrosine kinases. 1222 44

The phenotype of mitogen-activated protein kinase-activated protein kinase-2 (MK2) knockout mice revealed the essential role of this enzyme in post-transcriptional regulation of lipopolysaccharide-induced expression of cytokines such as tumour necrosis factor (TNF)-alpha, interleukin-6 and interferon-gamma, at the level of mRNA stability and translation. In the case of TNF-alpha, this regulation depends on the AU-rich element in TNF-alpha mRNA. In addition to cytokine expression, MK2 is also essential for cell migration in vitro. Although the role of MK2 in cytokine expression depends mainly on catalytic activity, its role in cell migration is also dependent on a proline-rich N-terminal motif. However, the molecular mechanisms involved and the relevant protein targets for MK2 are not completely defined. Here we discuss the possible mechanisms by which two potential target proteins of MK2, small heat-shock protein 25/27 (Hsp25/27) and tristetraprolin, could contribute to our understanding of the above regulation.
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PMID:Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? 1244 Sep 54


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