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Query: UNIPROT:P06889 (Mol)
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In a previous study, we had shown that activation of the AT2 (angiotensin type 2) receptor of angiotensin II (Ang II) induced morphological differentiation of the neuronal cell line NG108-15. In the present study, we investigated the nature of the possible intracellular mediators involved in the AT2 effect. We found that stimulation of AT2 receptors in NG108-15 cells resulted in time-dependent modulation of tyrosine phosphorylation of a number of cytoplasmic proteins. Stimulation of NG108-15 cells with Ang II induced a decrease in GTP-bound p21ras but a sustained increase in the activity of p42mapk and p44mapk as well as neurite outgrowth. Similarly, neurite elongation, increased polymerized tubulin levels, and increased mitogen-activated protein kinase (MAPK) activity were also observed in a stably transfected NG108-15 cell line expressing the dominant-negative mutant of p21ras, RasN17. These results support the observation that inhibition of p21ras did not impair the effect of Ang II on its ability to stimulate MAPK activity. While 10 microM of the MEK inhibitor, PD98059, only moderately affected elongation, 50 microM PD98059 completely blocked the Ang II- and the RasN17-mediated induction of neurite outgrowth. These results demonstrate that some of the events associated with the AT2 receptor-induced neuronal morphological differentiation of NG108-15 cells not only include inhibition of p21ras but an increase in MAPK activity as well, which is essential for neurite outgrowth.
Mol Endocrinol 1999 Sep
PMID:Signals from the AT2 (angiotensin type 2) receptor of angiotensin II inhibit p21ras and activate MAPK (mitogen-activated protein kinase) to induce morphological neuronal differentiation in NG108-15 cells. 1047 50

Part of the cellular response to toxins, physical stresses and inflammatory cytokines occurs by signalling via the stress-activated protein kinase (SAPK) and p38 reactivating kinase pathways. This results in modification of cellular gene expression. These stress-responsive kinase pathways are structurally similar, but functionally distinct, from the archetypal mitogen-activated protein kinases (MAPKs or ERKs). The ERK pathway is a hierarchical cascade originating at the cell membrane with receptors for mitogens or growth factors, which recruit, via adapter proteins and exchange factors, the small guanosine triphosphatase (GTPase) Ras (see fig. 1). Ras activates raf, a serine threonine kinase, which activates MEK (MAPK/ERK kinase). MEK, in turn, phosphorylates and activates ERK1 and ERK2, which translocate to the nucleus and transactivate transcription factors, changing gene expression to promote growth, differentiation or mitosis. By transducing signals through a cascade of kinases, several options for control are introduced for amplifying and/or modifying the output signal. The SAPK and p38 pathways are also hierarchically arranged, but less is known about the upstream components and the downstream effects of stimulation of these pathways. Among the processes modulated by stress-responsive pathways are apoptosis, transformation, development, immune activation, inflammation and adaptation to environmental changes. This review outlines the upstream componentry of these pathways that interact with a variety of agonists to modify the activity of SAPK and p38, and explores the downstream functions of this activation.
Cell Mol Life Sci 1999 Aug 15
PMID:The stress-activated protein kinase pathways. 1048 5

Expression of constructs encoding fusion proteins of ERK1 and ERK2 containing a C-terminal farnesylation motif (CAAX) is predominantly localized at the cell membrane and was activated by coexpression of constitutively active Ha-RasL61 and epidermal growth factor. Both fusion proteins significantly inhibit the transcriptional activation of a c-fos-chloramphenicol acetyltransferase reporter induced by RasL61, constitutively active MEK1, or constitutively active RafBXB. The corresponding SAAX chimeras or overexpression of the wild-type ERKs did not interfere with the transcriptional activation of c-fos. The inhibition of the Ras-mediated c-fos induction by ERK2-CAAX can in part be rescued by coexpression of a wild-type ERK2 but not by wild-type ERK1. We find that ERK1-CAAX acts in the same fashion, indicating that mitogen-activated protein kinase (MAPK)-CAAX chimeras interact in an isotype-specific manner. It is demonstrated that both ERK1-CAAX and ERK2-CAAX associate with the corresponding endogenous ERKs, which explains the isotype-specific inhibitory effects of the ERK-CAAX chimeras. Evidence is presented that expression of ERK-CAAX fusion proteins inhibits the nuclear translocation of the corresponding endogenous ERKs. Disruption of MAPK translocation by membrane targeting provides additional, independent proof that nuclear translocation of ERKs is essential for the transcriptional activation of c-fos.
Mol Cell Biol 1999 Dec
PMID:Novel membrane-targeted ERK1 and ERK2 chimeras which act as dominant negative, isotype-specific mitogen-activated protein kinase inhibitors of Ras-Raf-mediated transcriptional activation of c-fos in NIH 3T3 cells. 1056 31

The synergism between insulin and prolactin (PRL) in their effect on protein synthesis in the mammary gland was studied in differentiating mammary epithelial CID-9 cells. Both hormones were needed to induce phosphorylation of PHAS-I which resulted in its dissociation from the eIF-4E translation initiation factor. This step is crucial for the initiation of translation. The induction of PHAS-I phosphorylation was rapid and its rate matched that demonstrated for the JAK2/STAT5a and the binding of STAT5a to its DNA binding motif. However, 120 min was needed for complete phosphorylation of the PHAS-I protein. In the presence of insulin, PRL induced MAP kinase activity, initiated at a comparable rate to that of PHAS-I phosphorylation. However, a line of evidence suggested that although this kinase phosphorylates PHAS-I in vitro, it does not actively participate in its phosphorylation in vivo: (a) the level of insulin needed to enable PRL-induced ERK-1/ERK-2 activation was one order of magnitude higher than that needed for PHAS-I phosphorylation; and (b) PD 098059, a MEK-1 inhibitor, completely inhibited insulin-dependent, PRL-induced ERK-1/ERK-2 activation but had no effect on the PRL-induced PHAS-I phosphorylation. In contrast, wortmannin, a phosphatidylinositol 3-kinase (PI 3'-kinase) inhibitor and the immunosuppressant rapamycin abrogated PHAS-I phosphorylation and caused a reciprocal shift between the fully phosphorylated PHAS-I gamma form and its non-phosphorylated alpha form. Since the partly phosphorylated PHAS-I beta form was not significantly affected by these inhibitors, it is possible that more than a single kinase mediates the synergistic effect of prolactin and insulin on PHAS-I phosphorylation.
Mol Cell Endocrinol 1999 Sep 10
PMID:Prolactin and insulin synergize to regulate the translation modulator PHAS-I via mitogen-activated protein kinase-independent but wortmannin- and rapamycin-sensitive pathway. 1058 Aug 37

Using combined immunofluorescence and fluorescence in situ hybridization (FISH) analysis we have extensively characterized the proteins associating with two different homologue human neocentromeres at interphase and prometaphase/metaphase, and compared these directly with those found with normal human centromeres. Antisera to CENP-A, CENP-B, CENP-C, CENP-E, CENP-F, INCENP, CLIP-170, dynein, dynactin subunits p150 (Glued) and Arp1, MCAK, Tsg24, p55CDC, HZW10, HBUB1, HBUBR1, BUB3, MAD2, ERK1, 3F3/2, topoisomerase II and a murine HP1 homologue, M31, were used in immuno-fluorescence experiments in conjunction with FISH employing specific DNA probes to clearly identify neocentromeric DNA. We found that except for the total absence of CENP-B binding, neocentromeres are indistinguishable from their alpha satellite-containing counterparts in terms of protein composition and distribution. This suggests that the DNA base of a potential centromeric locus is of minimal importance in determining the overall structure of a functional kinetochore and that, once seeded, the events leading to functional kinetochore formation occur independently of primary DNA sequence.
Hum Mol Genet 2000 Jan 22
PMID:Human centromeres and neocentromeres show identical distribution patterns of >20 functionally important kinetochore-associated proteins. 1060 28

Initial biochemical signaling originating from high-affinity immunoglobulin E receptor (FcepsilonRI) has been ascribed to Src family kinases. To understand the mechanisms by which individual kinases drive the signaling, we conducted reconstitution experiments: FcepsilonRI signaling in RBL2H3 cells was first suppressed by a membrane-anchored, gain-of-function C-terminal Src kinase and then reconstructed with Src family kinases whose C-terminal negative regulatory sequence was replaced with a c-myc epitope. Those constructs derived from Lyn and Fyn, which are associated with detergent-resistant membranes (DRMs), physically interacted with resting FcepsilonRI and reconstructed clustering-induced signaling that leads to calcium mobilization and ERK1 and -2 activation. c-Src-derived construct, which was excluded from DRMs, failed to interact with FcepsilonRI and to restore the signaling, whereas creation of palmitoylatable Cys3 enabled it to interact with DRMs and with FcepsilonRI and to restore the signaling. Deletion of Src homology 3 (SH3) domain from the Lyn-derived construct did not alter its ability to transduce the series of signaling. Deletion of SH2 domain did not affect its association with DRMs and with FcepsilonRI nor clustering-induced tyrosine phosphorylation of FcepsilonRI beta and gamma subunits, but it almost abrogated the next step of tyrosine phosphorylation of Syk and its recruitment to FcepsilonRI. These findings suggest that Lyn and Fyn could, but c-Src could not, drive FcepsilonRI signaling and that N-terminal palmitoylation and SH2 domain are required in sequence for the initial interaction with FcepsilonRI and for the signal progression to the molecular assembly.
Mol Cell Biol 2000 Mar
PMID:Sequential requirements of the N-terminal palmitoylation site and SH2 domain of Src family kinases in the initiation and progression of FcepsilonRI signaling. 1066 52

Atherosclerosis is an inflammatory disease mediated through the action of monocyte/macrophages, complement and T-lymphocytes. C5a and monocyte chemotactic factor released during complement activation in the arterial wall may participate in the initial monocyte recruitment. Assembly of C5b-9 on cells of the arterial wall may also induce cell lysis. On the other hand, sublytic assembly of C5b-9 on smooth muscle cells (SMC) and endothelial cells (EC) induces cell activation and proliferation. Analysis of mitogen activated protein kinases (MAPK) pathways induced by C5b-9 in aortic SMC revealed that extracellular signal regulated kinase (ERK) 1, c-jun NH2-terminal kinase (JNK) 1, and p38 MAPK are all activated by C5b-9. ERK1 activity was inhibited by wortmannin suggesting that ERK1 pathway is activated through phosphatidyl inositol -3 (PI 3-) kinase. Sublytic C5b-9 assembly on the plasma membrane was also able to activate Janus kinase (JAK) 1, signal transducer and activator (STAT) 3 and STAT4 in EC. JAK1 but not STAT3 activation induced by C5b-9 is dependent on Gi protein activation. New evidence accumulated during the last decade support the role of complement activation in both initiation and progression of the atherosclerotic lesions. Complement system activation is a major component of the chronic inflammatory process associated with atherosclerosis.
Mol Immunol
PMID:Complement activation and atherosclerosis. 1069 49

The in vivo effects of bis(maltolato)oxovanadium (IV) (BMOV) on the activity of protein serine kinases in skeletal muscle of STZ-diabetic Wistar rats were studied. BMOV was administered to STZ-diabetic rats at a concentration of 0.75 mg/ml for 8 weeks. Chronic BMOV treatment completely normalized plasma glucose levels in the diabetic animals after 8 weeks of treatment. Insulin-stimulated ERK-1 and ERK-2 activity was markedly increased in STZ-diabetic rats. Chronic BMOV treatment normalized the activity of ERK-2 in the diabetic treated animals, whereas the activity of ERK-1 was unaffected. In contrast to ERK-1 and ERK-2, the activity of the ribosomal S6 kinase p90rsk was decreased in STZ-diabetic rats. BMOV treatment restored the activity to normal levels. Basal p70 S6K activity was increased about 2.5-fold in the untreated diabetic group and no further increase in activity was observed after insulin stimulation. BMOV treatment did not correct the changes in p70 S6K activity in either the basal or insulin-stimulated states. In conclusion (i) the activity of ERK-1, ERK-2 and p90rsk were altered in skeletal muscle of STZ-diabetic rats; (ii) the glucoregulatory effects of BMOV were accompanied by concurrent improvement in the activities of ERK-2 and p90rsk; and (iii) there appears to be a dissociation between the activation of ERK-2 and p90rsk, suggesting that the regulation of p90rsk may be much more complex in vivo.
Mol Cell Biochem 1999 Dec
PMID:Effects of bis(maltolato) oxovanadium (IV) on protein serine kinases in skeletal muscle of streptozotocin-diabetic rats. 1070 3

A variety of G protein-coupled receptors (GPCRs) are phosphorylated by G protein-coupled receptor kinase 2 (GRK2). This event promotes the binding of regulatory proteins termed beta-arrestins to GPCRs, leading to uncoupling from G proteins and receptor internalization. Recent data indicate that GRK2 and beta-arrestins also play an important role in the stimulation of the extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinase (MAPK) cascade by GPCRs. In this report, we have investigated the existence of functional interactions between GRK2 and MAPK. We show that activation of beta(2)-adrenergic receptors (beta(2)-AR) promotes the rapid association of GRK2 and MAPK in living cells, as assessed by coimmunoprecipitation experiments in COS-7 cells transfected with beta(2)-AR, GRK2, and an epitope-tagged MAPK. Coimmunoprecipitation of MAPK and GRK2 is blocked by inhibition of the MAPK cascade and is not observed upon activation of MAPK in the absence of beta(2)-AR stimulation, thus indicating that both an active MAPK and agonist occupancy of GPCR are required for the association to occur. Interestingly, we have found that purified ERK1/MAPK can directly phosphorylate the C-terminal domain of GRK2, and that the phosphorylation process is favored by the presence of Gbetagamma-subunits or an activated receptor. Furthermore, GRK2 phosphorylation by MAPK leads to a decreased activity of GRK2 toward GPCR. Taken together, our results suggest that stimulation of GPCRs promotes the rapid association of GRK2 and MAPK leading to modulation of GRK2 functionality, thus putting forward a new feedback mechanism for the regulation of GPCR signaling.
Mol Pharmacol 2000 Apr
PMID:Agonist-dependent modulation of G protein-coupled receptor kinase 2 by mitogen-activated protein kinases. 1072 25

In addition to their ability to stimulate cell proliferation, polypeptide growth factors are able to maintain cell survival under conditions that otherwise lead to apoptotic death. Growth factors control cell viability through regulation of critical intracellular signal transduction pathways. We previously characterized C2 muscle cell lines that lacked endogenous expression of insulin-like growth factor II (IGF-II). These cells did not differentiate but underwent apoptotic death in low-serum differentiation medium. Death could be prevented by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we analyze the signaling pathways involved in growth factor-mediated myoblast survival. PDGF treatment caused sustained activation of extracellular-regulated kinases 1 and 2 (ERK1 and -2), while IGF-I only transiently induced these enzymes. Transient transfection of a constitutively active Mek1, a specific upstream activator of ERKs, maintained myoblast viability in the absence of growth factors, while inhibition of Mek1 by the drug UO126 blocked PDGF-mediated but not IGF-stimulated survival. Although both growth factors activated phosphatidylinositol 3-kinase (PI3-kinase) to similar extents, only IGF-I treatment led to sustained stimulation of its downstream kinase, Akt. Transient transfection of a constitutively active PI3-kinase or an inducible Akt promoted myoblast viability in the absence of growth factors, while inhibition of PI3-kinase activity by the drug LY294002 selectively blocked IGF- but not PDGF-mediated muscle cell survival. In aggregate, these observations demonstrate that distinct growth factor-regulated signaling pathways independently control myoblast survival. Since IGF action also stimulates muscle differentiation, these results suggest a means to regulate myogenesis through selective manipulation of different signal transduction pathways.
Mol Cell Biol 2000 May
PMID:Dual control of muscle cell survival by distinct growth factor-regulated signaling pathways. 1075 9


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