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71.
Silvia Jansen Maria Andries Rita Derua Etienne Waelkens Mathieu Bollen 《The Journal of biological chemistry》2009,284(21):14296-14302
Autotaxin or NPP2 (nucleotide pyrophosphatase/phosphodiesterase 2) is a
secreted lysophospholipase-D that promotes metastasis and tumor growth by its
ability to generate lysophosphatidic acid. Considerable evidence suggests that
inhibitors of NPP2 can be used as a novel therapy for the treatment of cancer.
Although most attention is currently directed toward the development of
inhibitors of the catalytic site, we have explored whether NPP2 can also be
targeted through its non-catalytic nuclease-like domain. We demonstrate here
that the catalytic and nuclease-like domains are covalently linked by an
essential disulfide bridge between Cys413 and Cys805.
Within the nuclease-like domain, residues 829–850 are involved in the
secretion of NPP2, and Lys852 is required for the expression of
catalytic activity. These data show that the nuclease-like domain is crucial
for catalysis by NPP2 and is a possible target to generate inhibitors.NPP2 3 or autotaxin
is a secreted lysophospholipase-D that acts in a paracrine or autocrine
manner. The major substrate of NPP2 is lysophosphatidylcholine, which is
converted into choline and lysophosphatidic acid. The latter promotes
signaling through specific G-protein-coupled receptors that stimulate cell
proliferation, differentiation, and motility
(1). NPP2 functions in
processes as diverse as the homing of lymphocytes, blood vessel formation, and
wound healing but also promotes tumorigenesis
(2–6).
The metastasis-enhancing properties of NPP2 have been attributed to its
ability to promote the invasive properties of cancer cells and to stimulate
angiogenesis. Importantly, NPP2 is highly expressed by various cancers
including breast carcinoma (7),
Hodgkin lymphoma (8), and
glioblastoma multiforme (9),
and this correlates with an increased metastasis and angiogenesis. Therefore,
NPP2 is considered to be an attractive target for a novel anticancer therapy,
in particular because it acts extracellularly, and interfering drugs thus do
not need to be cell-permeable
(10).NPP2 is one of the seven mammalian members of the NPP-type family of
ectophosphodiesterases, belonging to the superfamily of
phospho-/sulfo-coordinating metalloenzymes
(11). These enzymes all have a
structurally related catalytic domain and the same catalytic mechanism but
show a different substrate specificity. For example, NPP1 only recognizes
nucleotide substrates, whereas NPP2 preferentially hydrolyzes
lysophospholipids. Interestingly, NPP1–3 share a C-terminal
non-catalytic domain, commonly referred to as the nuclease-like domain (NLD)
(12). The latter is related to
DNA/RNA-nonspecific endonucleases but lacks key residues that are necessary
for activity and is therefore believed to have a structural or regulatory
role. It is not known whether the NLD acts as a positive or negative regulator
of NPP activity, but swapping experiments of the NLD between NPP1 and NPP2
suggested that it harbors isoform-specific determinants for catalysis
(13).To examine the therapeutic potential of NPP2, in particular for the
treatment of cancer, a number of small molecule inhibitors have been developed
(14,
15). However, these inhibitors
are all directed against the catalytic site and may therefore also interfere
with other phospho-/sulfo-coordinating metalloenzymes. We report here that the
NLD is essential for the expression of catalytic activity and can be used as
an alternative target to inhibit NPP2. 相似文献
72.
Søeborg T Ganderup NC Kristensen JH Bjerregaard P Pedersen KL Bollen P Hansen SH Halling-Sørensen B 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2006,834(1-2):117-121
A straightforward analytical method for determination of 3-benzylidene camphor (3-BC) in rat adipose tissue, brain, liver, muscle, plasma and testis following topical application was developed and validated. Three exposure levels (60, 180 and 540 mg kg(-1) day(-1)) were tested for 65 days in male Sprague-Dawley rats (24 days postnatal). Sample preparation involving homogenization and n-heptane or methanol extraction of the tissue was applied before injection into the LC-ESI-MS-MS system. The response was linear from 2 to 100 microg l(-1) for the qualifier and the quantifier MRM transitions (R(2) (quantifier) > 0.994). Detection limit of the method corresponded to 0.005 microg g(-1) tissue and 12.5 microg l(-1) plasma, respectively. Recovery was determined for all tissues (adipose tissue: 40%; all other tissues: 80-100%) at three individual levels. 3-(4-Methyl benzylidene camphor) (4-MBC) was used throughout the study as internal standard. 3-Benzylidene camphor was detected in all tissues at all exposure levels at concentrations between 0.05 microg g(-1) (liver) and 36 microg g(-1) (adipose tissue) and in plasma at 16-89 microg l(-1). The method allowed for the quantification of 3-benzylidene camphor in all tested tissues following topical application. Furthermore, it was shown that 3-benzylidene camphor can be found in various tissues in the rat following topical application. These findings may suggest that following use of 3-benzylidene camphor containing sunscreen, similar disposition and distribution may occur in humans. 相似文献
73.
Wakula P Beullens M van Eynde A Ceulemans H Stalmans W Bollen M 《The Biochemical journal》2006,400(2):377-383
It is reasonably well understood how the initiation of translation is controlled by reversible phosphorylation of the eukaryotic translation initiation factors eIF2alpha, eIF2Bepsilon and eIF4E. Other initiation factors, including eIF2beta, are also established phosphoproteins but the physiological impact of their phosphorylation is not known. Using a sequence homology search we found that the central region of eIF2beta contains a putative PP1-(protein phosphatase-1) binding RVxF-motif. The predicted eIF2beta-PP1 interaction was confirmed by PP1 binding and co-immunoprecipitation assays on cell lysates as well as with the purified components. Site-directed mutagenesis showed that eIF2beta contains, in addition to an RVxF-motif, at least one other PP1-binding site in its C-terminal half. eIF2beta functioned as an inhibitor for the dephosphorylation of glycogen phosphorylase and Ser51 of eIF2alpha by PP1, but did not affect the dephosphorylation of Ser464 of eIF2Bepsilon by this phosphatase. Strikingly, eIF2beta emerged as an activator of its own dephosphorylation (Ser2, Ser67, Ser218) by associated PP1, since the substrate quality of eIF2beta was decreased by the mere mutation of its RVxF-motif. These results make eIF2beta an attractive candidate substrate for associated PP1 in vivo. The overexpression of wild-type eIF2beta or eIF2beta with a mutated RVxF-motif did not differentially affect the rate of translation, indicating that the binding of PP1 is not rate-limiting for translation under basal conditions. 相似文献
74.
75.
76.
Boudrez A Beullens M Groenen P Van Eynde A Vulsteke V Jagiello I Murray M Krainer AR Stalmans W Bollen M 《The Journal of biological chemistry》2000,275(33):25411-25417
NIPP1 is a regulatory subunit of a species of protein phosphatase-1 (PP1) that co-localizes with splicing factors in nuclear speckles. We report that the N-terminal third of NIPP1 largely consists of a Forkhead-associated (FHA) protein interaction domain, a known phosphopeptide interaction module. A yeast two-hybrid screening revealed an interaction between this domain and a human homolog (CDC5L) of the fission yeast protein cdc5, which is required for G(2)/M progression and pre-mRNA splicing. CDC5L and NIPP1 co-localized in nuclear speckles in COS-1 cells. Furthermore, an interaction between CDC5L, NIPP1, and PP1 in rat liver nuclear extracts could be demonstrated by co-immunoprecipitation and/or co-purification experiments. The binding of the FHA domain of NIPP1 to CDC5L was dependent on the phosphorylation of CDC5L, e.g. by cyclin E-Cdk2. When expressed in COS-1 or HeLa cells, the FHA domain of NIPP1 did not affect the number of cells in the G(2)/M transition. However, the FHA domain blocked beta-globin pre-mRNA splicing in nuclear extracts. A mutation in the FHA domain that abolished its interaction with CDC5L also canceled its anti-splicing effects. We suggest that NIPP1 either targets CDC5L or an associated protein for dephosphorylation by PP1 or serves as an anchor for both PP1 and CDC5L. 相似文献
77.
When stimulated by glucose, the pancreatic beta-cell displays large oscillations of intracellular free Ca2+ concentration ([Ca2+]i). To control [Ca2+]i, the beta-cell must be equipped with potent mechanisms for Ca2+ extrusion. We studied the expression of the plasma membrane Ca(2+)-ATPases (PMCA) in three insulin secreting preparations (a pure beta-cell preparation, RINm5F cells and pancreatic islet cells), using reverse-transcribed PCR, RNase protection assay and Western blotting. The four main isoforms, PMCA1, PMCA2, PMCA3 and PMCA4 were expressed in the three preparations. Six alternative splice mRNA variants, characterized at splice sites A, B and C were detected in the three preparations (rPMCA1xb, 2yb, 2wb, 3za, 3zc, 4xb), plus two additional variants in pancreatic islet cells (PMCA4za, 1xkb). The latter variant corresponded to a novel variant of rat PMCA1 gene lacking the exon coding for the 10th transmembrane segment, at splice site B. At the mRNA and protein level, five variants predominated (1xb, 2wb, 3za, 3zc, 4xb), whilst one additional isoform (4za), predominated at the protein level only. This provides the first evidence for the presence of PMCA2 and PMCA3 isoforms at the protein level in non-neuronal tissue. Hence, the pancreatic beta-cell is equipped with multiple PMCA isoforms with possible differential regulation, providing a full range of PMCAs for [Ca2+]i regulation. 相似文献
78.
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