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)

CD44 is the major cell surface receptor for the extracellular matrix glycosaminoglycan hyaluronan and is implicated in a variety of biological events that include embryonic morphogenesis, lymphocyte recirculation, inflammation, and tumor metastasis. CD44 delivers activation signals to T lymphocytes, B lymphocytes, natural killer cells, polymorphonuclear leukocytes, and macrophages by stimulating protein tyrosine phosphorylation and calcium influx. The mechanism of signal transduction via CD44 remains undefined, although CD44 was shown to physically associate with intracellular protein tyrosine kinase Lck in T lymphocytes. In the present report, we show that a significant proportion of CD44 in human peripheral blood T lymphocytes and endothelial cells is associated with low-density plasma membrane fractions that represent specialized plasma membrane domains enriched in glycosphingolipids and glycosylphosphatidylinositol (GPI)-anchored proteins. CD44 and the GPI-anchored CD59 do not appear to directly interact in the low-density membrane fractions. In human peripheral blood T lymphocytes, 20% to 30% of the Src family protein tyrosine kinases, Lck and Fyn, are recovered from these fractions. CD44-associated protein kinase activity was selectively recovered from the low-density membrane fractions, corresponding to glycosphingolipid-rich plasma membrane microdomains. Reprecipitation of the in vitro phosphorylated proteins showed that CD44 associates not only with Lck but also with Fyn kinase in these membrane domains. Our results suggest that cellular stimulation via CD44 may proceed through the signaling machinery of glycosphingolipid-enriched plasma membrane microdomains and, hence, depend on the functional integrity of such domains.
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PMID:CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes. 957 28

We have recently shown that the degradation products of hyaluronan of 3 to 10 disaccharides (o-HA), but not native high molecular weight hyaluronan, can induce angiogenesis in vivo and, as such, o-HA is an important regulator of the neovascularization process. As a continuation of this work, we have studied the cytoplasmic signal transduction pathways responsible for o-HA-activated endothelial cell proliferation. We show that the addition of o-HA (1 microg/ml) to bovine aortic endothelial cells induces tyrosine phosphorylation of multiple proteins within 1 minute and that the activity remains above basal levels for at least 24 hours. Increased phosphorylation of the CD44 receptor was also observed. Pretreatment of cells with an anti-CD44-receptor antibody (5 microg/ml) or the tyrosine kinase inhibitor genistein (10 microM) inhibited both o-HA-induced proliferation (p < 0.05) and protein tyrosine phosphorylation. In comparison, native hyaluronan had little effect on tyrosine phosphorylation across the same time period. Protein kinase C (PKC) activity was increased 2- to 3-fold in the membranes of cells treated with o-HA, and a pretreatment with phorbol 12,13-dibutyrate (PDBu) to down-regulate PKC significantly inhibited o-HA-induced cell proliferation (p < 0.05). Examination by Western blotting showed that only the betaI and epsilon isoforms remained translocated to the membrane for at least 24 hours. These isoforms seem to be involved in modulating the proliferative effects of o-HA, because the transient translocation of PKC isoforms by PDBu was not sufficient to induce mitogenesis. Furthermore, we show that PKC activation of the cytoplasmic kinase cascade (Raf-1 kinase, MAP kinase kinase [MEK-1], and extracellular signal-regulated kinase [ERK-1]) by o-HA culminated in the nuclear translocation of ERK-1. This pathway is essentially linear, as shown by the ability of specific enzyme inhibitors (PDBu and PD98059) to prevent both activation of ERK-1- and o-HA-induced proliferation. We conclude that phosphorylation of the CD44 receptor results in an increase in tyrosine phosphorylation, leading to the activation of a cytoplasmic cascade and cell proliferation; this concurs with previous work, which showed that o-HA-induced proliferation of endothelial cells is CD44-receptor-mediated and accompanied by early response gene activation.
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PMID:Angiogenic oligosaccharides of hyaluronan induce protein tyrosine kinase activity in endothelial cells and activate a cytoplasmic signal transduction pathway resulting in proliferation. 971 86

CD44, the predominant vertebrate cell surface receptor for hyaluronan, exists in a variety of isoforms resulting from alternative splicing of a single gene. Particular spliced variants of CD44 correlate with increased cell motility, and with poor clinical prognosis in several kinds of carcinomas. Combinations of 9 variant exons that confer this enhanced motility on tumor cells are inserted into a single site in the middle of the extracellular domain of CD44. Evidence suggests that phosphorylation of 2 serine residues in the intracellular domain of CD44 are involved in controlling these events. However, evidence is lacking as to the nature of such kinases. Acidic amino acids in close proximity to these 2 serine residues suggests casein kinase II (CKII) is involved. We now show an antisense phosphorothioate oligonucleotide designed to hybridize to the AUG translation initiation codon of subunit CKII alpha' mRNA blocks in vivo phosphorylation of CD44 in MDA231 breast tumor cells, and at the protein level decreases ectopic expression of total CD44 as well as the metastatic v-7 CD44 isoform. Furthermore subplateau RT-PCR analysis demonstrated antisense transfected MDA231 tumor cells had significant down-regulated or eliminated mRNA transcripts of metastatic CD44 isoforms. CKII as a CD44-associated serine kinase therefore may serve as an important molecule in a signaling cascade that produces a variety of cellular responses in MDA231 breast cancer cells. Since the 3'-untranslated region of CD44 mRNA contain 4 dispersed AUUUA sequences which serve as signals targeting mRNA for rapid turnover, a mechanism is proposed by which CD44 phosphorylation mediates labile message stabilization, hence providing insights into the processes involved in cancer cell growth, invasion and metastasis.
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PMID:Phosphorylation stabilizes alternatively spliced CD44 mRNA transcripts in breast cancer cells: inhibition by antisense complementary to casein kinase II mRNA. 978 39

CD44 appears to be involved in signal transduction, however, the mechanism of this function is unclear. Protein kinase activity was detected in neutrophils associated with CD44. Most of the protein kinase activity associated with these antigens was tyrosine kinase activity. Src family kinases lyn and hck were found to account for much of the associated tyrosine kinase activity. The data suggest that associated tyrosine kinase activity may play a role in signal transduction from CD44 in neutrophils to regulate other cell functions.
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PMID:Tyrosine kinase activity is associated with CD44 in human neutrophils. 984 86

To investigate the hypothesis that protein kinase Calpha (PKCalpha) is functional glial tumor cell invasion, stable PKCalpha sense and antisense transfected U-87 cell lines were established and PKCalpha expression characterized by Western blot and PKC activity assays. Invasion assays including barrier migration (Koochekpour et al., Extracellular matrix proteins inhibit proliferation, upregulate migration and induce morphological changes in human glioma lines. Eur. J. Cancer, 1995, 31, 375-380; Merzak et al., CD44 mediates human glioma cell adhesion and invasion in vitro. Cancer Res., 1994, 54, 3988-3992; Merzak et al., Cell surface gangliosides are involved in the control of human glioma cell invasion in vitro. Neurosci. Lett., 1994, 177, 11-16), and spheroid confrontation were used to study the relationship between PKCalpha expression and invasiveness. PKCalpha overexpressing clones show increased barrier migration (1.5x) relative to the control transfected clones. PKCalpha inhibited clones exhibited reduced invasiveness, to < 50%. In coculture with PKCalpha overexpressing clones, the remaining normal fetal rat brain aggregate volume was significantly decreased (up to 200%) but 90% of the initial brain volume was left in PKCalpha inhibited clone in the rat brain aggregate tumor spheroid confrontation. This effect was not associated with significant growth inhibition. We conclude that expression of PKCalpha in glioma-derived cell lines appears to be central to glioma invasion in vitro.
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PMID:The role of protein kinase Calpha in U-87 glioma invasion. 1057 7

Ligation of cell surface matrix adhesion receptors such as integrins can increase expression of specific cell cycle regulatory proteins such as cyclin A, thereby regulating cell cycle progression. Disruption of cell surface matrix receptor interaction with the extracellular matrix can trigger apoptosis. Induction of apoptosis has been linked to unscheduled up-regulation of cyclin A and activation of cyclin-A-associated dependent kinase 2 activity due to cleavage of cyclin-dependent kinase inhibitors by caspases. We have found that ligation of the cell surface matrix adhesion receptor CD44 by anti-CD44 antibody induces cell detachment and triggers apoptosis. In this report we show that ligation of CD44 by anti-CD44 antibody increases the expression of cyclin A protein prior to activation of caspase-3-like activity and morphological changes of apoptosis. Down-regulation of cyclin A protein levels by cyclin A antisense oligonucleotides dramatically decreased fibroblast apoptosis in response to anti-CD44 antibody. These data identify an important functional role of cyclin A in the induction of fibroblast apoptosis due to the ligation of the cell surface adhesion receptor CD44 by anti-CD44 antibody.
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PMID:Functional role of cyclin A on induction of fibroblast apoptosis due to ligation of CD44 matrix receptor by anti-CD44 antibody. 1085 61

Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption. Emk(-/-) mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4(+)T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. As Emk(-/-) animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.
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PMID:Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase. 1128 24

Polymorphonuclear cells (PMNs) contribute to the initiation and progression of the immune response by mediating cytotoxicity, phagocytosis, and cytokine secretion. Because CD44 serves as a cytotoxic-triggering molecule on PMNs, it was hypothesized that it could also trigger cytokine production. In this study, the effect of anti-CD44 antibodies on interleukin-6 (IL-6) production in human PMNs was assessed. By using a reverse transcriptase-polymerase chain reaction, it was shown that PMNs stimulated with a mouse monoclonal or a rabbit polyclonal F(ab)(2) anti-CD44 transcribe IL-6 messenger RNA. A similar effect was obtained when an anti-CD44 antibody was replaced with hyaluronic acid (HA). Kinetic studies showed that anti-CD44 and HA induced IL-6 gene transcription, initiated 3 hours after stimulation, peaked between 12 and 24 hours, and disappeared after 48 hours. Analogous results were achieved when secreted IL-6 protein was measured by enzyme-linked immunosorbent assay in the PMN culture supernatants. To characterize which metabolic pathways regulated CD44-dependent IL-6 production in PMNs, an RNA polymerase inhibitor, actinomycin D, and 2 protein kinase inhibitors, such as genistein and staurosporine, were tested. Actinomycin D and genistein blocked IL-6 production, whereas staurosporine did not, suggesting that CD44-dependent IL-6 production requires gene transcription and tyrosine kinase activity. Furthermore, the relationship between CD44 and cytokines that affect PMN function, including interferon gamma (IFNgamma) and IL-2, was investigated. Without CD44 cross-linking, IFNgamma did not trigger IL-6 production. However, on CD44 cross-linking, IFNgamma produced a strong synergistic effect on IL-6 syntheses in human PMNs. (Blood. 2001;97:3621-3627)
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PMID:CD44 ligation on peripheral blood polymorphonuclear cells induces interleukin-6 production. 1136 59

The cellular lineage of sinonasal T/NK (natural killer) cell lymphoma remains controversial. Lineage assignment is difficult because T cells and NK cells have a similar morphology and surface markers. Consequently, the assignment must depend heavily on the status of T-cell receptor (TCR) rearrangement. A monoclonal TCR rearrangement supports a T lineage; however, a corresponding monoclonality test for NK cells has not yet been established. Each NK cell bears a distinct set of killer cell immunoglobulin (Ig)-like receptors (KIRs) that are randomly distributed over three groups. In principle, restriction of the KIR repertoire signifies a monoclonal or possibly oligoclonal NK-cell proliferation, just as Ig light-chain restriction usually indicates a monoclonal B-cell neoplasm. Using a novel group-specific reverse transcriptase-polymerase chain reaction, we found a restricted KIR repertoire in most sinonasal lymphomas (9 of 10), but only rarely in T-cell lymphomas (2 of 10) or reactive conditions involving T/NK cells (1 of 10). KIR+ sinonasal lymphomas usually lacked a monoclonal TCR-gamma rearrangement pattern, expressed another NK cell receptor, NKG2a, and were usually CD56-positve, cyclin-dependent kinase-6 (CDK6)-positive, CD44-negative, a phenotype already reported to indicate a true NK cell lineage. We conclude that, although sinonasal lymphomas have heterogeneous genotypes and phenotypes, a restricted KIR repertoire without TCR-gamma rearrangement provides preliminary support for the monoclonality hypothesis and can be used for defining a true NK-cell lineage in a subset of sinonasal lymphomas.
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PMID:Restricted killer cell immunoglobulin-like receptor repertoire without T-cell receptor gamma rearrangement supports a true natural killer-cell lineage in a subset of sinonasal lymphomas. 1169 28

In this study we have investigated hyaluronan (HA)-CD44 interaction with protein kinase N-gamma (PKNgamma), a small GTPase (Rac1)-activated serine/threonine kinase in human keratinocytes. By using a variety of biochemical and molecular biological techniques, we have determined that CD44 and PKNgamma kinase (molecular mass approximately 120 kDa) are physically linked in vivo. The binding of HA to keratinocytes promotes PKNgamma kinase recruitment into a complex with CD44 and subsequently stimulates Rac1-mediated PKNgamma kinase activity. The Rac1-activated PKNgamma in turn increases threonine (but not serine) phosphorylation of phospholipase C (PLC) gamma1 and up-regulates PLCgamma1 activity leading to the onset of intracellular Ca(2+) mobilization. HA/CD44-activated Rac1-PKNgamma also phosphorylates the cytoskeletal protein, cortactin, at serine/threonine residues. The phosphorylation of cortactin by Rac1-PKNgamma attenuates its ability to cross-link filamentous actin in vitro. Further analyses indicate that the N-terminal antiparallel coiled-coil (ACC) domains of PKNgamma interact directly with Rac1 in a GTP-dependent manner. The binding of HA to CD44 induces PKNgamma association with endogenous Rac1 and its activity in keratinocytes. Transfection of keratinocytes with PKNgamma-ACCcDNA reduces HA-mediated recruitment of endogenous Rac1 to PKNgamma and blocks PKNgamma activity. These findings suggest that the PKNgamma-ACC fragment acts as a potent competitive inhibitor of endogenous Rac1 binding to PKNgamma in vivo. Most important, the PKNgamma-ACC fragment functions as a strong dominant-negative mutant that effectively inhibits HA/CD44-mediated PKNgamma phosphorylation of PLCgamma1 and cortactin as well as keratinocyte signaling (e.g. Ca(2+) mobilization and cortactin-actin binding) and cellular functioning (e.g. cell-cell adhesion and differentiation). Taken together, these findings strongly suggest that hyaluronan-CD44 interaction with Rac1-PKNgamma plays a pivotal role in PLCgamma1-regulated Ca(2+) signaling and cortactin-cytoskeleton function required for keratinocyte cell-cell adhesion and differentiation.
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PMID:Hyaluronan-CD44 interaction with Rac1-dependent protein kinase N-gamma promotes phospholipase Cgamma1 activation, Ca(2+) signaling, and cortactin-cytoskeleton function leading to keratinocyte adhesion and differentiation. 1512 40


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