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)

The casein kinase I (CKI) family consists of at least seven vertebrate genes, some of which can be alternatively spliced. Previously, we have studied the four splice variants of the chicken CKIalpha gene. The four proteins differ only by the presence or absence of two peptides, a 28-amino-acid "L" insert in the catalytic domain and a 12-amino-acid "S" insert near the extreme C-terminus. Here cells were transfected with DNA encoding all four isoforms fused to the green fluorescent protein (GFP) and the localization of each protein was examined. We noted that the L insert includes the sequence PVGKRKR, which has the characteristics of a nuclear localization signal (NLS), and we show that the CKIalphaL and CKIalphaLS isoforms which contain this sequence are targeted to the nucleus, where a fraction becomes associated with nuclear speckles. In contrast the two isoforms lacking the L insert remain predominantly cytoplasmic. Mutation of the first lysine in the putative NLS to asparagine prevented the nuclear entry of GFP-CKIalphaL. Therefore different CKIalpha isoforms are targeted to different cellular compartments in a fashion modulated by alternate transcription and in these locations presumably phosphorylate and regulate different cellular substrates.
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PMID:Four casein kinase I isoforms are differentially partitioned between nucleus and cytoplasm. 1157 Aug 20

Human chromosomal region 11p15 is known to be associated with several diseases including predispositions to develop various tumor types. In search of candidate genes, a novel human kinase gene is described, STK33, which codes for a serine/threonine protein kinase. The gene was discovered by comparative genome analysis of human chromosome 11p15.3 and its orthologous region on distal mouse chromosome 7. Human STK33 gene contains 12 exons as has been determined by the comparison to the full-length transcript amplified from human uterus RNA. Transcripts are found in a variety of tissues in at least two alternatively spliced forms as revealed by reverse transcriptase-polymerase chain reaction, cDNA sequencing and expressed sequence tag clustering. Phylogenetic analysis suggests that STK33 may belong to the calcium/calmodulin-dependent protein kinase group, even though, like several other members of the group, it lacks the calcium/calmodulin binding domain [FASEB J. 9 (1995) 576]. STK33 shows a differential expression in a variety of normal and malignant tissues.
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PMID:A novel serine/threonine kinase gene, STK33, on human chromosome 11p15.3. 1173 31

Two novel alternatively spliced isoforms of the human two-pore-domain potassium channel TREK-2 were isolated from cDNA libraries of human kidney and fetal brain. The cDNAs of 2438 base pairs (bp) (TREK-2b) and 2559 bp (TREK-2c) encode proteins of 508 amino acids each. RT-PCR showed that TREK-2b is strongly expressed in kidney (primarily in the proximal tubule) and pancreas, whereas TREK-2c is abundantly expressed in brain. In situ hybridization revealed a very distinct expression pattern of TREK-2c in rat brain which partially overlapped with that of TREK-1. Expression of TREK-2b and TREK-2c in human embryonic kidney (HEK) 293 cells showed that their single-channel characteristics were similar. The slope conductance at negative potentials was 163 +/- 5 pS for TREK-2b and 179 +/- 17 pS for TREK-2c. The mean open and closed times of TREK-2b at -84 mV were 133 +/- 16 and 109 +/- 11 micros, respectively. Application of forskolin decreased the whole-cell current carried by TREK-2b and TREK-2c. The sensitivity to forskolin was abolished by mutating a protein kinase A phosphorylation site at position 364 of TREK-2c (construct S364A). Activation of protein kinase C (PKC) by application of phorbol-12-myristate-13-acetate (PMA) also reduced whole-cell current. However, removal of the putative TREK-2b-specific PKC phosphorylation site (construct T7A) did not affect inhibition by PMA. Our results suggest that alternative splicing of TREK-2 contributes to the diversity of two-pore-domain K+ channels.
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PMID:Expression pattern and functional characteristics of two novel splice variants of the two-pore-domain potassium channel TREK-2. 1189 36

In the nervous system, inositol 1,4,5-trisphosphate (IP(3)) is one of the second messengers produced by PI hydrolysis and triggers IP(3)-receptor (IP(3)R) mediated calcium release from intracellular pools. Throughout the brain, the type 1 IP(3)R is predominantly expressed and its mRNA is widely distributed. Alternative splicing of IP(3)R1 (SI and SII) occurs in two distinct regions. SI splicing in the middle of the ligand binding domain may alter the IP(3) binding activity, while SII splicing probably affects the protein kinase A phosphorylation sites and kinetics. Selective use of IP(3)-receptor subtypes may permit a tissue specific and developmentally specific expression of functionally distinct channels. The present work was focused on detection of the alternatively spliced mRNA of type 1 IP(3)-receptor in individual brain structures and nuclei. Using RT-PCR we detected neuronal (535bp) and non-neuronal (410bp) forms. We identified both spliced variants in the majority of brain structures, except in the cerebellum and medulla. In the cerebellum, the neuronal form of type 1 IP(3)R was found exclusively, while in the medulla, the non-neuronal form was much more abundant. Nevertheless, Western blot analysis and hybridization with specific antibody against IP(3)R revealed no qualitative, but only quantitative differences. Similarly, IP(3) dependent calcium release did not show any differences between the cerebellum and pons. These results demonstrate the distribution of alternatively spliced S2 variants of type 1 IP(3)R in selected brain structures and nuclei. The physiological relevance of these two forms remains to be elucidated by further studies.
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PMID:Distribution of neuronal and non-neuronal spliced variants of type 1 IP(3)-receptor in rat hypothalamus and brain stem. 1191 73

Ca2+/calmodulin (CaM)-dependent protein kinase (CaMKII) is a ubiquitous mediator of Ca2+-linked signalling that phosphorylates a wide range of substrates to co-ordinate and regulate Ca2+-mediated alterations in cellular function. The transmission of information by the kinase from extracellular stimuli and the intracellular Ca2+ rise is not passive. Rather, its multimeric structure and autoregulation enable this enzyme to participate actively in the sensitivity, timing and location of its action. CaMKII can: (i) be activated in a Ca2+-spike frequency-dependent manner; (ii) become independent of its initial Ca2+/CaM activators; and (iii) undergo a 'molecular switch-like' behaviour, which is crucial for certain forms of learning and memory. CaMKII is derived from a family of four homologous but distinct genes, with over 30 alternatively spliced isoforms described at present. These isoforms possess diverse developmental and anatomical expression patterns, as well as subcellular localization. Six independent catalytic/autoregulatory domains are connected by a narrow stalk-like appendage to each hexameric ring within the dodecameric structure. Ca2+/CaM binding activates the enzyme by disinhibiting the autoregulatory domain; this process initiates an intra-holoenzyme autophosphorylation reaction that induces complex changes in the enzyme's sensitivity to Ca2+/CaM, including the generation of Ca2+/CaM-independent (autonomous) activity and marked increase in affinity for CaM. The role of CaMKII in Ca2+ signal transduction is shaped by its autoregulation, isoenzymic type and subcellular localization. The molecular determinants and mechanisms producing these processes are discussed as they relate to the structure-function of this multifunctional protein kinase.
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PMID:Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. 1193 44

One of the molecular mechanisms shown to have played a major role in orchestrating the expression of the many genes with unique cellular and temporal specificity in spermatogenesis, is the cAMP-dependent signaling pathway. In this pathway, gene expression is mediated primarily by two members of the bZIP transcription factors-cAMP-response element binding protein (CREB) and cAMP-responsive element modulator (CREM). Both bind a specific cis element, cAMP-response element (CRE), in the promoter of target genes, both are activated by protein kinase A (PKA) phosphorylation that enables binding of CREB binding protein (CBP) and recruitment of the basal transcription machinery, and both are characterized by multiple alternatively spliced forms. Some of these alternatively spliced forms lack the transactivation domains and hence function as transcription suppressors. In Sertoli cells, CREB levels fluctuate in a cyclical manner that depends on the specific cell associations along the spermatogenic wave. Follicle stimulating hormone (FSH) activates the cAMP signaling pathway and consequently, CREB positively auto-regulates its own expression (by binding to a CRE like element in its promoter). Subsequently, activated CREB activates transcription of genes essential for proper germ cell differentiation. In addition, TNFalpha secreted by round spermatids, activates NF-kappaB dependent CREB expression in Sertoli cells and thus, contributes to the elevated CREB levels as long as these cells are intimately associated. Inducible cAMP early repressor (ICER), a suppressor isoform of CREM, also activated by CREB, down regulates CREB expression together with its own expression, resetting CREB to basal level that enables a new spermatogenic wave. In germ cells, antagonist forms of CREM (alpha, beta and gamma) are present in premeiotic cells and early prophase spermatocytes. A prominent switch to the CREMtau and CREMtheta; activating forms starts in pachytene spermatocytes leading to the activation of haploid genes important for spermiogenesis in round spermatids. Interestingly, in germ cells, CREM exerts activation of haploid genes independent of its phosphorylation state. It associates with activator of CREM in testis (ACT), that has an intrinsic transcriptional activity, rather than with CBP. These and other findings suggest that the expanding CREB/CREM proteins and potentially other members of the CREB family are key molecular regulators at all stages of spermatogenesis.
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PMID:The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis. 1198 18

The partitioning-defective 3 (par3) gene encodes a protein with three postsynaptic density90/DiscslargeA/ZO-1 (PDZ) domains that is required for cell polarity establishment in metazoans. Par3 is a component of a protein complex that can include Cdc42-GTP, Par6 and atypical protein kinase Cs (aPKCs). We now describe the identification of a related human gene, Par3L. Both Par3L and Par3 are expressed as numerous alternatively spliced variants. Although Par3 expression appears to be ubiquitous, that of Par3L is more restricted. Multiple variants are often expressed simultaneously within a specific cell type or tissue. Although all of the Par3L/Par3 isoforms can associate with tight junctions in epithelial cells, they show different binding properties. No Par3L isoforms and only a subset of Par3 isoforms detectably bind aPKCs. These data suggest that aPKC binding or phosphorylation is not required for targeting of Par3/Par3L to cell-cell contacts. Par3L isoforms also show differential binding to Par6. Despite these differences, the N-terminal region of Par3L, like that of Par3, can disrupt the formation of tight junctions when ectopically expressed in Madin-Darby canine kidney (MDCK) cells.
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PMID:Multiple splice variants of Par3 and of a novel related gene, Par3L, produce proteins with different binding properties. 1223 71

Phosducin-like protein (PhLP) is a member of the phosducin family of G-protein betagamma-regulators and exists in two splice variants. The long isoform PhLP(L) and the short isoform PhLP(S) differ by the presence or absence of an 83-amino acid N terminus. In isolated biochemical assay systems, PhLP(L) is the more potent Gbetagamma-inhibitor, whereas the functional role of PhLP(S) is still unclear. We now report that in intact HEK 293 cells, PhLP(S) inhibited Gbetagamma-induced inositol phosphate generation with approximately 20-fold greater potency than PhLP(L). Radiolabeling of transfected HEK 293 cells with [(32)P] revealed that PhLP(L) is constitutively phosphorylated, whereas PhLP(S) is not. Because PhLP(L) has several consensus sites for the constitutively active kinase casein kinase 2 (CK2) in its N terminus, we tested the phosphorylation of the recombinant proteins by either HEK cell cytosol in the presence or absence of kinase inhibitors or by purified CK2. PhLP(L) was a good CK2 substrate, whereas PhLP(S) and phosducin were not. Progressive truncation and serine/threonine to alanine mutations of the PhLP(L) N terminus identified a serine/threonine cluster (Ser-18/Thr-19/Ser-20) within a small N-terminal region of PhLP(L) (amino acids 5-28) as the site in which PhLP(L) function was modified in HEK 293 cells. In native tissue, PhLP(L) also seems to be regulated by phosphorylation because phosphorylated and non-phosphorylated forms of PhLP(L) were detected in mouse brain and adrenal gland. Moreover, the alternatively spliced isoform PhLP(S) was also found in adrenal tissue. Therefore, the physiological control of G-protein regulation by PhLP seems to involve phosphorylation by CK2 and alternative splicing of the regulator.
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PMID:Regulation of phosducin-like protein by casein kinase 2 and N-terminal splicing. 1246 82

Alternative splicing of RNA transcripts is a general characteristic for NCX genes in mammals, mollusks, and arthropods. Among the family of three NCX genes in mammals, the NCX1 gene contains six exons, namely, A, B, C, D, E, and F, that make up the alternatively spliced region. Studies of the NCX1 gene transcripts suggested that 16 distinct gene products can be produced from the NCX1 gene. The exons A and B are mutually exclusive when expressed. Generally, exon A-containing transcripts are predominantly found in excitable cells like cardiomyoctes and neurons, whereas exon B-containing transcripts are mostly found in nonexcitable cells like astrocytes and kidney cells. Other alternatively spliced exons (C-F) appear to be cassette-type exons and are found in various combinations. Interestingly, exon D is present in all characterized transcripts. The alternatively spliced isoforms of NCX1 show tissue-specific expression patterns, suggesting functional adaptation to tissues. To investigate functional differences among alternatively spliced isoforms of NCX1, we expressed an exon A-containing transcript present in cardiac tissue (NCX1.1) and an exon B-containing transcript found in the kidney (NCX1.3) in Xenopus oocytes. We demonstrated that the Na(+)/Ca(2+) exchangers expressed by exon A- and exon B-containing transcripts display differences in activation by PKA and by [Ca(2+)](i). We also observed that these two isoforms show differences in voltage dependence. Surprisingly, the alternatively spliced isoforms of NCX1 display greater functional differences among themselves than the products of different gene loci, NCX1, NCX2, and NCX3.
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PMID:Functional regulation of alternatively spliced Na+/Ca2+ exchanger (NCX1) isoforms. 1250 60

The intracellular role of placental protein 17b (PP17b)/TIP47 has been controversial, because it is considered to be a protein required for mannose 6-phosphate receptor transport from endosome to trans-Golgi as well as a neutral lipid droplet-associated protein. The similarity between the amino acid sequences of PP17 variants, adipophilin and perilipins, and between their gene structures indicate that PP17b as well as other alternatively spliced PP17 variants belong to the lipid storage droplet protein family, containing also some differentiation factors. Using a specific antibody, PP17b was detected in lipid droplet fractions and co-localized with neutral lipid droplets stained by Nile red, and fluorescently labelled PP17 antibody in HeLa cells with confocal microscopy. PP17b was also detected in milk, associated to milk lipid globule membranes. Cytostatic agents induced apoptosis and PP17b synthesis in HeLa cells, which was significantly inhibited by protein kinase C (PKC) inhibitor, indicating the involvement of NF-kappa B and AP-1 transcription factors in this process, while protein kinase A (PKA) inhibitor had only a modest inhibitory effect. Cell differentiation induced by dibutyryl cyclic AMP or phorbol myristate acetate also increased PP17b synthesis, demonstrating its strong involvement in cell differentiation. PP17b synthesis was higher in M than in G0/G1 phases in control, apoptotic and differentiated cells. This data shows that PP17b is a neutral lipid droplet-associated protein, and its expression is regulated by PKC- and PKA-dependent pathways.
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PMID:Lipid droplet and milk lipid globule membrane associated placental protein 17b (PP17b) is involved in apoptotic and differentiation processes of human epithelial cervical carcinoma cells. 1263 Dec 76


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