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:2.7.11.25 (MEKK1)
1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TGF-beta inhibits the growth of many cell types, including hematopoietic cells and lymphocytes. TGF-beta transduces signals through two different types of serine/threonine kinase receptors, type I (T beta R-I) and type II (T beta R-II). T beta R-II is a primary binding protein for the ligands, and T beta R-I is an effector protein, which determines the specificity of signals. Type III receptor (betaglycan) and endoglin play more indirect roles; i.e. delivery of ligands to the signaling receptors. Various molecules, including farnesyl transferase-alpha, Mothers against dpp (Mad)-related proteins, and a novel MAPKKK (TAK1), have been suggested to participate in the signal transduction of TGF-beta receptors. TGF-beta receptors and Mad-related proteins have been found to act as tumor suppressor genes in various tumors, including colorectal cancers and T-cell lymphoma.
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PMID:TGF-beta receptors and signal transduction. 907 13

Recent studies have revealed that mitogen-activated protein kinase (MAPK) consists of at least three subfamilies, namely classical MAPK (also known as ERK), stress-activated protein kinase/c-Jun N-terminal kinase (JNK) and p38 kinase. TGF-beta-activating kinase (TAK)-1 is a novel MAPKKK which is reported to stimulate p38K and/or the JNK pathway. To elucidate the functional roles of the TAK1 pathway, we transfected its constitutive active form (TAK1dN) and negative form (TAK1K63W) into LLC-PK1 cells. TAKdN inhibited [3H]thymidine uptake and reduced the percentages of S and G2/M phases. TAK1K63W ameliorated the inhibitory effects of TGF-beta on [3H]thymidine uptake and increased the percentages of S and G2/M phases. Western blot analysis demonstrates that the level of cyclin D1 protein was regulated negatively by overexpression of TAK1dN. Moreover, overexpression of TAK1dN inhibited cyclin D1 promoter activity. In contrast, constitutive active MKK1, the classical p42/44 MAPK activator, increased cyclin D1 promoter activity and level of protein. Overexpression of the active form of MKK1 increased [3H]thymidine uptake, while the inactive form decreased the uptake. In conclusion, cyclin D1 promoter activity and cell cycle progression are regulated negatively by the TAK1 pathway and positively by the classical MAPK pathway.
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PMID:Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK. 1004 49

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.
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PMID:p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. 1078 14

Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.
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PMID:The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. 1212 19

TGF-beta activated kinase 1 (TAK1) is a MAP kinase kinase kinase (MAPKKK) that has been shown to function downstream of BMPs and TGF-beta (J. Biol. Chem. 275 (2000) 17647; EMBO J. 17 (1998) 1019; Science 270 (1995) 2008), as well as in the interleukin-1 (IL-1) signaling pathway (J. Biol. Chem. 276 (2001) 3508; Nature 398 (1999) 252). Using immunohistochemistry (IHC), we demonstrate that TAK1 is expressed ubiquitously during early development. At mid-gestation, TAK1 expression becomes more restricted, with high levels seen specifically during development of diverse organs and tissues including the nervous system, testis, kidney, liver and gut. Additionally, TAK1 expression is seen in the developing lung and pancreas. Our results suggest that TAK1 may play multiple roles in mouse development.
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PMID:Expression of TAK1, a mediator of TGF-beta and BMP signaling, during mouse embryonic development. 1271 37

Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGFbeta or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation.
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PMID:Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. 1582 Jun 71

Transforming growth factor-beta1 (TGF-beta1) alters myocardial gene expression, resulting in myocyte hypertrophy, through activation of TGF-beta-activated kinase (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family. We hypothesized that the TGF-beta1-TAK1-p38 MAPK pathway might be activated during ventricular remodeling after myocardial infarction (MI). One, 3, 7, and 14 days after ligation of the left anterior descending coronary artery, noninfarcted left ventricular tissue samples were obtained. Protein levels as well as mRNA levels of the signaling pathway, TGF-beta1, TGF-beta-receptors, and TAK1 increased in the noninfarcted myocardium in MI rats compared with sham-operated animals. Phosphorylation of MAPKK 3/6 (MKK3/6) and p38 MAPK, the downstream targets of TAK1, was also increased in the noninfarcted region. Moreover, an in vitro kinase assay revealed that the activated TAK1 in the noninfarcted myocardium was capable of activating recombinant MKK3/6, suggesting a causative role of TAK1 in the remodeling process. The activation of the TGF-beta1-TAK1-p38 MAPK pathway paralleled the transcriptional upregulation of cardiac markers for ventricular hypertrophy, beta-myosin heavy chain and atrial natriuretic peptide. TAK1 was mainly localized to cardiomyocytes, whereas TGF-beta1 receptors were observed in vascular smooth muscle cells and fibroblasts as well as cardiomyocytes. Thus the TGF-beta1-TAK1-MKK3/6-p38 MAPK pathway in the cardiomyocytes of noninfarcted spared myocardium is activated after acute MI and may play an important role in ventricular hypertrophy and post-MI remodeling in rats.
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PMID:Activation of TGF-beta1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats. 1618 34

TGF-beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-kappaB and AP-1 and, therefore, plays a crucial role in regulating the genes that mediate inflammation. Although in vitro biochemical studies have revealed the existence of a TAK1 complex, which includes TAK1 and the adapter proteins TAB1 and TAB2, it remains unclear which members of this complex are essential for signaling. To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality. Using embryonic fibroblasts lacking TAK1, TAB1, or TAB2, we have found that TNFR1, IL-1R, TLR3, and TLR4-mediated NF-kappaB and AP-1 activation are severely impaired in Tak1(m/m) cells, but they are normal in Tab1(-/-) and Tab2(-/-) cells. In addition, Tak1(m/m) cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-alpha and IL-1 signaling pathways, where it functions downstream of RIP1-TRAF2 and MyD88-IRAK1-TRAF6, respectively. However, TAK1 is not required for NF-kappaB activation through the alternative pathway following LT-beta signaling. In the TGF-beta signaling pathway, TAK1 deletion leads to impaired NF-kappaB and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF-beta-induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKKbeta and JNK, but not IKKalpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.
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PMID:TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. 1626 Apr 93

IL-1 plays a major role in inflammation and autoimmunity through activation of nuclear factor kappa B (NFkappaB) and MAPKs. Although a great deal is known about the mechanism of activation of NFkappaB and MAPKs by IL-1, much less is known about the down-regulation of this pathway. Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown. We show here that SOCS-3 inhibits NFkappaB-dependent transcription induced by overexpression of the upstream IL-1 signaling molecules MyD88, IL-1R-activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFbeta-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1.
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PMID:Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. 1654 9

TGFbeta activated kinase 1 (TAK1) is a MAPKKK that in cell culture systems has been shown to act downstream of a variety of signaling molecules, including TGFbeta. Its role during vertebrate development, however, has not been examined by true loss-of-function studies. In this report, we describe the phenotype of mouse embryos in which the Tak1 gene has been inactivated by a genetrap insertion. Tak1 mutant embryos exhibit defects in the developing vasculature of the embryo proper and yolk sac. These defects include dilation and misbranching of vessels, as well as an absence of vascular smooth muscle. The phenotype of Tak1 mutant embryos is strikingly similar to that exhibited by loss-of-function mutations in the TGFbeta type I receptor Alk1 and the type III receptor endoglin, suggesting that TAK1 may be a major effector of TGFbeta signals during vascular development. Consistent with this view, we find that in zebrafish, morpholinos to TAK1 and ALK1 synergize to enhance the Alk1 vascular phenotype. Moreover, we show that overexpression of TAK1 is able to rescue the vascular defect produced by morpholino knockdown of ALK1. Taken together, these results suggest that TAK1 is probably an important downstream component of the TGFbeta signal transduction pathway that regulates vertebrate vascular development. In addition, as heterozygosity for mutations in endoglin and ALK1 lead to the human syndromes known as hereditary hemorrhagic telangiectasia 1 and 2, respectively, our results raise the possibility that mutations in human TAK1 might contribute to this disease.
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PMID:The TGF beta activated kinase TAK1 regulates vascular development in vivo. 1655 14


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