Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TGF-beta modulates immune responses by regulating T cell function. The Smad family of proteins has been recently shown to transduce signals for the TGF-beta superfamily and Smad2 mediates TGF-beta signaling. Here, we showed that TGF-beta phosphorylated Smad2 and induced interaction between Smad2 and Smad4 in primary T cells and the Jurkat T cell line. Interestingly, ligation of the T cell receptor (TCR)/CD3 complex with anti-CD3 mAb also phosphorylated Smad2, but failed to induce interaction between Smad2 and Smad4 in the Jurkat T cell line. Phosphorylation of Smad2 via the TCR/CD3 complex was not abrogated by treatment with neutralizing antibody against TGF-beta. Furthermore, PD98059, a MEK inhibitor, suppressed Smad2 phosphorylation by stimulation with anti-CD3 mAb in Jurkat T cell line. These findings indicated that not only TGF-beta but also stimulation via the TCR/CD3 complex phosphorylated Smad2 through mitogen-activated protein (MAP) kinase cascades, suggesting that Smad2 may function in both TGF-beta- and TCR/CD3 complex-mediated signaling pathways in T cells.
 ...
PMID:Ligation of the T cell receptor complex results in phosphorylation of Smad2 in T lymphocytes. 1065 24

Members of the transforming growth factor beta (TGF-beta) family transduce signals through Smad proteins. Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca(2+)-calmodulin. Here we report that Smad-TGF-beta-dependent transcriptional responses are prevented by expression of a constitutively activated Ca(2+)-calmodulin-dependent protein kinase II (Cam kinase II). Smad2 is a target substrate for Cam kinase II in vitro at serine-110, -240, and -260. Cam kinase II induces in vivo phosphorylation of Smad2 and Smad4 and, to a lesser extent, Smad3. A phosphopeptide antiserum raised against Smad2 phosphoserine-240 reacted with Smad2 in vivo when coexpressed with Cam kinase II and by activation of the platelet-derived growth factor receptor, the epidermal growth factor receptor, HER2 (c-erbB2), and the TGF-beta receptor. Furthermore, Cam kinase II blocked nuclear accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization independently of TGF-beta receptor activation, while preventing TGF-beta-dependent Smad2-Smad3 interactions. These findings provide a novel cross-talk mechanism by which Ca(2+)-dependent kinases activated downstream of multiple growth factor receptors antagonize cell responses to TGF-beta.
 ...
PMID:Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. 1102 80

The signaling capabilities and biological functions of activin receptor-like kinase 7 (ALK7), a type I receptor serine/threonine kinase predominantly expressed in the nervous system, are unknown. We have constructed a cell line derived from the rat pheochromocytoma PC12 in which expression of a constitutively active mutant of ALK7 (T194D) is under the control of a tetracycline-inducible promoter. For comparison, another cell line was engineered with tetracycline-regulated expression of a constitutively active variant of the transforming growth factor-beta type I receptor ALK5. Expression of activated ALK7 in PC12 cells resulted in activation of Smad2 and Smad3, but not Smad1, as well as the mitogen-activated protein kinases extracellular signal-regulated kinase and c-Jun N-terminal kinase. Reporter assays demonstrated that ALK7 activation stimulates transcription from the Smad-binding element of the Jun-B gene, the plasminogen activator inhibitor-1 gene, and AP-1 elements. In addition, ALK7 activation induced expression of endogenous gene products, including Smad7, c-fos mRNA, and plasminogen activator inhibitor-1. Thymidine incorporation assays revealed an anti-proliferative effect of ALK7 activation in PC12 cells, which correlated with increased transcription from the promoters of cycline-dependent kinase inhibitors p15(INK4B) and p21. Unexpectedly, ALK7 signaling produced a remarkable change in cell morphology characterized by cell flattening and elaboration of blunt, short cell processes. Interestingly, no such changes were observed upon induction of activated ALK5. The alterations in cell morphology upon ALK7 activation were more pronounced in cultures grown in full serum, were accompanied by rearrangements of actin filaments, and were maintained for several days after withdrawal of treatment. PC12 cultures that had been "primed" in this way showed an accelerated and augmented differentiation response to nerve growth factor. These results indicate that ALK7 may participate in the control of proliferation of neuronal precursors and morphological differentiation of postmitotic neurons.
 ...
PMID:The orphan receptor serine/threonine kinase ALK7 signals arrest of proliferation and morphological differentiation in a neuronal cell line. 1108 22

Transforming growth factor (TGF)-beta promotes breast cancer metastasis to bone. To determine whether the osteolytic factor parathyroid hormone-related protein (PTHrP) is the primary mediator of the tumor response to TGF-beta, mice were inoculated with MDA-MB-231 breast cancer cells expressing a constitutively active TGF-beta type I receptor. Treatment of the mice with a PTHrP-neutralizing antibody greatly decreased osteolytic bone metastases. There were fewer osteoclasts and significantly decreased tumor area in the antibody-treated mice. TGF-beta can signal through both Smad and mitogen-activated protein (MAP) kinase pathways. Stable transfection of wild-type Smad2, Smad3, or Smad4 increased TGF-beta-stimulated PTHrP secretion, whereas dominant-negative Smad2, Smad3, or Smad4 only partially reduced TGF-beta-stimulated PTHrP secretion. When the cells were treated with a variety of protein kinases inhibitors, only specific inhibitors of the p38 MAP kinase pathway significantly reduced both basal and TGF-beta-stimulated PTHrP production. The combination of Smad dominant-negative blockade and p38 MAP kinase inhibition resulted in complete inhibition of TGF-beta-stimulated PTHrP production. Furthermore, TGF-beta treatment of MDA-MB-231 cells resulted in a rapid phosphorylation of p38 MAP kinase. Thus, the p38 MAP kinase pathway appears to be a major component of Smad-independent signaling by TGF-beta and may provide a new molecular target for anti-osteolytic therapy.
 ...
PMID:Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. 1196 7

We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor-beta (TGF-beta) receptor serine/threonine kinases, in TGF-beta-dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HL-60. TGF-beta-dependent differentiation of these cells to monocytes, but not retinoic acid-dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3. Vitamin D(3) also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1. Simultaneous treatment of these cells with TGF-beta1 and all-trans-retinoic acid (ATRA), which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-beta1 alone. TGF-beta1 and ATRA activate P42/44 mitogen-activated protein (MAP) kinase with nearly identical kinetics, ruling out its involvement in these effects on Smad phosphorylation. Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL-60R mutant cells, which harbor a defective retinoic acid receptor-alpha (RAR-alpha), ATRA is unable to reduce levels of TGF-beta-induced phospho-Smad2/3, coincident with its inability to differentiate these cells along granulocytic pathways. Together, these data suggest a new level of cross-talk between ATRA and TGF-beta, whereby a putative RAR-alpha-dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-beta, ultimately reducing the levels of nuclear Smad complexes mediating the TGF-beta-dependent differentiation of the cells to monocytic end points.
 ...
PMID:Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. 1239 16

Earlier studies have implicated the significance of transforming growth factor-beta3 (TGFbeta3) in the regulation of Sertoli cell tight junction (TJ) dynamics, possibly via its inhibitory effects on the expression of occludin, claudin-11, and zonula occludens-1 (ZO-1). Yet the mechanism by which TGFbeta3 regulates the Sertoli cell TJ-permeability barrier is not known. Using techniques of semiquantitative reverse transcription-PCR (RT-PCR), immunoblotting, immunohistochemistry, and inhibitors against different kinases coupled with physiological techniques to assess the Sertoli cell TJ barrier function, it was shown that this TGFbeta3-induced effect on Sertoli cell TJ dynamics is mediated via the p38 mitogen-activated protein (MAP) kinase pathway. First, the assembly of the Sertoli cell-TJ barrier was shown to be associated with a transient but significant decline in both the TGFbeta3 production and expression by Sertoli cells. Furthermore, addition of TGFbeta3 to Sertoli cell cultures during TJ assembly indeed perturbed the TJ barrier with an IC50 at approximately 9 pM. Second, the TGFbeta3-induced disruption of the TJ barrier was associated with a transient induction in MEKK2 but not the other upstream signaling molecules that mediate TGFbeta3 action, such as Smad2, Cdc42, Rac2, and N-Ras, suggesting this effect might be mediated via the p38 MAP kinase pathway. This postulate was confirmed by the observation that TGFbeta3 also induced the protein level of the activated and phosphorylated form of p38 MAP kinase at the time the TJ barrier was perturbed. Third, and perhaps the most important of all, this TGFbeta3-mediated inhibitory effect on the TJ barrier and the TGFbeta3-induced p-p38 MAP kinase production could be blocked by SB202190, a specific p38 MAP kinase inhibitor, but not U0126, a specific MEK1/2 kinase inhibitor. These results thus unequivocally demonstrate that TGFbeta3 utilizes the p38 MAP kinase pathway to regulate Sertoli cell TJ dynamics.
 ...
PMID:Transforming growth factor beta3 regulates the dynamics of Sertoli cell tight junctions via the p38 mitogen-activated protein kinase pathway. 1260 50

While it is thought that advanced glycation end products (AGEs) act by stimulating transforming growth factor (TGF)-beta to mediate diabetic injury, we report that AGEs can activate TGF-beta signaling, Smads, and mediate diabetic scarring directly and independently of TGF-beta. AGEs activate Smad2/3 in renal and vascular cells at 5 min, peaking over 15-30 min before TGF-beta synthesis at 24 h and occurs in TGF-beta receptor I and II mutant cells. This is mediated by RAGE and ERK/p38 mitogen-activated protein kinases (MAPKs). In addition, AGEs also activate Smads at 24 h via the classic TGF-beta-dependent pathway. A substantial inhibition of AGE-induced Smad activation and collagen synthesis by ERK/p38 MAPK inhibitors, but not by TGF-beta blockade, suggests that the MAPK-Smad signaling crosstalk pathway is a key mechanism in diabetic scarring. Prevention of AGE-induced Smad activation and collagen synthesis by overexpression of Smad7 indicates that Smad signaling may play a critical role in diabetic complications. This is further supported by the findings that activation of Smad2/3 in human diabetic nephropathy and vasculopathy is associated with local deposition of AGEs and up-regulation of RAGE. Thus, AGEs act by activating Smad signaling to mediate diabetic complications via both TGF-beta-dependent and -independent pathways, shedding new light on the pathogenesis of diabetic organ injury.
 ...
PMID:Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. 1270 99

Transforming growth factor betas (TGF-betas) regulate key aspects of embryonic development and major human diseases. Although Smad2, Smad3, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs) have been proposed as key mediators in TGF-beta signaling, their functional specificities and interactivity in controlling transcriptional programs in different cell types and (patho)physiological contexts are not known. We investigated expression profiles of genes controlled by TGF-beta in fibroblasts with ablations of Smad2, Smad3, and ERK MAPK. Our results suggest that Smad3 is the essential mediator of TGF-beta signaling and directly activates genes encoding regulators of transcription and signal transducers through Smad3/Smad4 DNA-binding motif repeats that are characteristic for immediate-early target genes of TGF-beta but absent in intermediate target genes. In contrast, Smad2 and ERK predominantly transmodulated regulation of both immediate-early and intermediate genes by TGF-beta/Smad3. These results suggest a previously uncharacterized hierarchical model of gene regulation by TGF-beta in which TGF-beta causes direct activation by Smad3 of cascades of regulators of transcription and signaling that are transmodulated by Smad2 and/or ERK.
 ...
PMID:Hierarchical model of gene regulation by transforming growth factor beta. 1293 Aug 90

Transforming growth factor (TGF)-beta1 is a member of a superfamily of multifunctional cytokines involved in several pathological processes of the kidney, including fibrogenesis, apoptosis and epithelial-mesenchymal transition. These events lead to tubulointerstitial fibrosis and glomerulosclerosis. Less is known about TGF-beta1-induced alterations of cell function. An important function of proximal tubular cells is reabsorption of filtered proteins, including albumin, via megalin-cubilin-dependent receptor-mediated endocytosis. In this study we used a well established cell culture model (proximal-tubule-derived opossum kidney (OK) cells) in order to test the hypothesis that TGF-beta1 reduces megalin-cubilin-mediated endocytosis. Previously we have shown that albumin endocytosis in OK cells is mediated by megalin/cubulin. TGF-beta1 led to a time- and dose-dependent downregulation of megalin-cubilin-mediated endocytosis without affecting two other transport systems tested. Binding, internalization and intracellular trafficking of the ligand albumin were affected. Decreased binding resulted from reduced cubilin and megalin expression in the 200 000 g membrane fraction. The underlying mechanism of TGF-beta1 action does not involve mitogen-activated protein kinases, protein kinase C or A, or reactive oxygen species. In contrast, TGF-beta1-induced downregulation of megalin-cubilin-mediated endocytosis was sensitive to inhibition of translation and transcription and was preceded by Smad2 and 3 phosphorylation. Dominant negative Smad2/3 constructs prevented the effect of TGF-beta1. In conclusion our data indicate that enhanced levels of TGF-beta1 occurring in various nephropathies can lead to downregulation of megalin-cubilin-dependent endocytosis. Probably, TGF-beta1 leads to Smad2- and Smad3-dependent expression of negative regulators of receptor-mediated endocytosis.
 ...
PMID:Transforming growth factor-beta1 reduces megalin- and cubilin-mediated endocytosis of albumin in proximal-tubule-derived opossum kidney cells. 1456 30

The thiazolidinedione (TZD) class of antidiabetic drugs, which are ligands for peroxisome proliferator-activated receptor (PPAR)-gamma, has been shown to possess potent anti-inflammatory and antineoplastic actions. Here, we show in mesangial cells that PPAR-gamma agonists inhibit fibronectin expression by transforming growth factor (TGF)-beta 1. TGF-beta 1 enhanced fibronectin mRNA expression, and this enhancement was abrogated by pretreatment with pioglitazone. Electrophoretic mobility shift assay identified that pioglitazone inhibited TGF-beta 1-induced DNA binding of activator protein-1 (AP-1). Pioglitazone inhibited AP-1 reporter activity but not Smad binding elements reporter activity without affecting TGF-beta 1-induced activation of mitogen-activated protein kinases (MAPKs) or Smad2. PPAR-gamma overexpression inhibited TGF-beta 1-induced fibronectin expression as well as the activation of AP-1. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a natural PPAR-gamma ligand, also inhibited TGF-beta1-induced fibronectin expression by suppressing AP-1 activation by TGF-beta 1. 15d-PGJ(2) inhibited the TGF-beta 1-induced MAPK activation. Dominant-negative PPAR-gamma (Delta PPAR-gamma) completely abrogated the inhibitory effect of pioglitazone and incompletely blocked its effect of 15d-PGJ(2) on TGF-beta 1-induced AP-1 reporter activity. Delta PPAR-gamma overexpression did not affect the inhibitory effect of 15d-PGJ(2) on TGF-beta 1-induced MAPK activation. In conclusion, pioglitazone inhibits TGF-beta 1-induced fibronectin expression by inhibiting AP-1 activation dependent on PPAR-gamma, while 15d-PGJ(2) acts through a dual mechanism independent of and dependent on PPAR-gamma activation in mouse mesangial cells.
 ...
PMID:Peroxisome proliferator-activated receptor-gamma ligands inhibit TGF-beta 1-induced fibronectin expression in glomerular mesangial cells. 1469 16


1 2 3 4 Next >>