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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the biological basis of tooth movement is crucial to orthodontics. Identifying the components of the signal transduction pathway initiated after force application will permit their manipulation, leading to better results. To examine the effects of mechanical stimulation in the periodontium, human periodontal ligament cells were isolated, cultured and characterized. In contrast to gingival fibroblasts, human PDL-fibroblasts in culture exhibit characteristics typical of osteoblast-like cells. To assess the role of mechanical stimulation the relevant orthodontic forces were simulated in vitro. For this purpose PDL-cells were cultured in Petri dishes with a flexible bottom. This bottom can be stretched over a convex template so that the adherent cells will be also stretched. The results of the stretching experiments demonstrate that human PDL-cells respond to mechanical stretch by a signal transduction pathway which most likely includes specific small GTP-binding proteins, such as Rab and Rho, as well as well defined transcription factors (c-Jun and c-Fos).
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PMID:Biological reactions to orthodontic tooth movement. 930 Aug 35

The Rho subfamily of low molecular weight GTPases have been implicated in a variety of cellular functions that include reorganization of the actin cytoskeleton and stress-induced activation of the c-Jun kinase. The downstream targets that mediate the effects of Cdc42 on the actin cytoskeleton have yet to be fully identified. We have used the transient transfection of COS-7 cells with epitope-tagged Cdc42 to identify candidate signaling partners for this GTPase and identified the IQGAP protein as a major in vivo target for activated Cdc42. Epidermal growth factor stimulation of serum-starved COS-7 cells promoted the formation of a Cdc42-IQGAP complex, indicating that growth factors can increase the pool of activated Cdc42. Activated HA-Cdc42 co-localized with IQGAP or F-actin in vivo, whereas cells transfected with dominant-negative forms of Cdc42 (Cdc42(T17N)) showed predominantly dispersed distributions for both HA-Cdc42 and endogenous IQGAP. In detergent lysates from COS-7 cells transiently transfected with different forms of Cdc42, or from stably transfected CHO cells, the induction of actin polymerization by phalloidin resulted in the incorporation of both IQGAP and Cdc42 into actin-containing complexes. Taken together, these findings are consistent with a model whereby IQGAP serves as a target for GTP-bound Cdc42 providing a direct link between the activated GTPase and the actin cytoskeleton.
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PMID:Identification of an actin cytoskeletal complex that includes IQGAP and the Cdc42 GTPase. 930 4

c-Jun NH2-terminal protein kinase (JNK), a distant member of the mitogen-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-activating kinase 1 (JNKK1), a dual specificity protein kinase that phosphorylates JNK on threonine 183 and tyrosine 185 residues. Here we show that JNKK2, a novel member of the MAP kinase kinase family, was phosphorylated and activated by MEKK1, a MAP kinase kinase kinase in the JNK signaling cascade. JNKK2 activity was also stimulated by constitutively active forms of Rac and Cdc42Hs, members of the Rho small GTP-binding protein family. Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK. Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1. The existence of multiple JNK-activating kinases may contribute to the specificity of the JNK signaling cascade.
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PMID:Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. 931 68

Exposure of mammalian cells to stressful stimuli results in activation of the c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinases (SAPKs), a family of protein kinases related to mitogen-activated protein (MAP) kinase. JNK/SAPKs are activated by specific MAP kinase kinases (MKKs), one of which, MKK4/SEK1, has been characterized extensively. In Drosophila, the JNK/SAPK Basket (Bsk) and the MKK Hemipterous (Hep), are important for embryonic development. Loss of function of either gene inhibits dorsal closure, a morphogenetic movement in which the edges of the embryonic ectoderm move together over the amnioserosa. There is evidence that the Rho GTPases Rac and Cdc42 are also required for dorsal closure, suggesting that Rac or Cdc42 may regulate Hep and Bsk. We have identified MKK7, a murine homolog of Hep. MKK7 functionally rescues hep mutant flies. In fibroblasts, MKK7 is activated by stress and by the GTPase Rac1. MKK7 directly phosphorylates and activates JNK/SAPK. Thus, MKK7 is a homolog of hep and functions in a conserved signaling pathway involving JNK/SAPK and the GTPase Rac1.
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PMID:MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. 931 5

Cdc42Hs is a small GTPase of the Rho-subfamily, which regulates signaling pathways that influence cell morphology and polarity, cell-cycle progression and transcription. An essential role for Cdc42Hs in cell growth regulation has been suggested by the finding that the Dbl oncoprotein is an upstream activator-a guanine nucleotide exchange factor (GEF)-for Cdc42Hs, and that activated mutants of the closely related GTPases Rac and Rho are transforming. As we were unable to obtain significant over-expression of GTPase-defective Cdc42Hs mutants, we have generated a mutant, Cdc42Hs(F28L), which can undergo spontaneous GTP-GDP exchange while maintaining full GTPase activity, and thus should exhibit functional activities normally imparted by Dbl. In cultured fibroblasts, Cdc42Hs(F28L) activated the c-Jun kinase (JNK1) and stimulated filopodia formation. Cells stably expressing Cdc42Hs(F28L) also exhibited several hallmarks of transformation-reduced contact inhibition, lower dependence on serum for growth, and anchorage-independent growth. Our findings indicate that Cdc42Hs plays a role in cell proliferation, and is a likely physiological mediator of Dbl-induced transformation.
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PMID:A novel Cdc42Hs mutant induces cellular transformation. 936 62

The small GTPase RhoB is immediate-early inducible by DNA damaging treatments and thus part of the early response of eukaryotic cells to genotoxic stress. To investigate the regulation of this cellular response, we isolated the gene for rhoB from a mouse genomic library. Sequence analysis of the rhoB gene showed that its coding region does not contain introns. The promoter region of rhoB harbors regulatory elements such as TATA, CAAT, and Sp1 boxes but not consensus sequences for AP-1, Elk-1, or c-Jun/ATF-2. The rhoB promoter was activated by UV irradiation, but not by 12-O-tetradecanoylphorbol-13-acetate treatment. rhoB promoter deletion constructs revealed a fragment of 0.17 kilobases in size which was sufficient in eliciting the UV response. This minimal promoter fragment contains TATA and CAAT boxes but no other known regulatory elements. Neither MEK inhibitor PD98059 nor p38 kinase inhibitor SB203580 blocked stimulation of rhoB by UVC (UV light, 254 nm) which indicates that ERK or p38 mitogen-activated protein (MAP) kinase are not involved in the UV induction of rhoB. Also, phosphatidylinositol 3-kinase inhibitor wortmannin, which blocks UV stimulation of both JNK and p38 MAP kinase, did not inhibit rhoB activation. Furthermore, activation of JNK by interleukin-1beta did not affect rhoB expression. These data indicate that JNK is not involved in the regulation of rhoB. Overexpression of wild-type Rac as well as the Rho guanine-dissociation inhibitor caused activation of rhoB. Wild-type RhoB inhibited both basal and UV-stimulated rhoB promoter activity, indicating a negative regulatory feedback by RhoB itself. The data provide evidence both for a signal transduction pathway independent of JNK, ERK, and p38 MAP kinase to be involved in the induction of rhoB by genotoxic stress, and furthermore, indicate autoregulation of rhoB.
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PMID:rhoB encoding a UV-inducible Ras-related small GTP-binding protein is regulated by GTPases of the Rho family and independent of JNK, ERK, and p38 MAP kinase. 938 98

An increase in the level of the c-Jun transcription factor and of its phosphorylation has previously been shown to be essential for nerve growth factor (NGF) withdrawal-induced apoptosis of rat sympathetic neurons (SCG). The Rho-like GTPases Cdc42 and Rac1 are involved in the regulation of a number of cellular processes, including activation of the c-Jun NH2-terminal kinase (JNK) pathway. Therefore, we have investigated the role of these GTPases in this process. Overexpression of activated Rac1 or Cdc42 in SCG neurons maintained in the presence of NGF induced apoptosis, whereas expression of dominant negative mutants of Cdc42 or Rac1 blocked apoptosis following NGF withdrawal. Cdc42 activation produced an increase in the level of c-Jun and of its phosphorylation. Furthermore, Cdc42-induced death was prevented by coexpressing the c-Jun dominant negative FLAGDelta169. Thus, Cdc42 appears to function as an initiator of neuronal cell death by activating a transcriptional pathway regulated by c-Jun.
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PMID:The small GTP-binding protein Cdc42 is required for nerve growth factor withdrawal-induced neuronal death. 952 Apr 79

The small GTP-binding proteins Ras, Rac, and Cdc42 link protein-tyrosine kinases with mitogen-activated protein kinase (MAPK) signaling cascades. Ras controls the activation of extracellular signal-regulated kinases (ERKs), while Rac and Cdc42 regulate the c-Jun N-terminal kinases (JNKs). In this study, we investigated whether small G protein/MAPK cascades contribute to signal transduction by transforming variants of c-Fes, a nonreceptor tyrosine kinase implicated in cytokine signaling and myeloid differentiation. First, we investigated the effects of dominant-negative small G proteins on Rat-2 fibroblast transformation by a retroviral homolog of c-Fes (v-Fps) and by c-Fes activated via N-terminal addition of the v-Src myristylation signal (Myr-Fes). We observed that dominant-negative Ras, Rac, and Cdc42 inhibited v-Fps- and Myr-Fes-induced growth of Rat-2 cells in soft agar, indicating that activation of these small GTP-binding proteins is required for fibroblast transformation by Fps/Fes tyrosine kinases. To determine whether MAPK pathways are activated downstream of these small G proteins, we measured ERK and JNK activity in the v-Fps- and Myr-Fes-transformed Rat-2 cells. Both ERK and JNK activities were elevated in the transformed cells, suggesting that these pathways are involved in cellular transformation. Dominant-negative mutants of Ras (but not Rac or Cdc42) specifically inhibited ERK activation by v-Fps and Myr-Fes, demonstrating that ERK activation occurs exclusively downstream of Ras. All three dominant-negative small G proteins inhibited JNK activation by v-Fps and Myr-Fes, indicating that JNK activation by these tyrosine kinases requires both Ras and Rho family GTPases. These data demonstrate that multiple small G protein/MAPK cascades are involved in downstream signal transduction by Fps/Fes tyrosine kinases.
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PMID:Fibroblast transformation by Fps/Fes tyrosine kinases requires Ras, Rac, and Cdc42 and induces extracellular signal-regulated and c-Jun N-terminal kinase activation. 959 27

The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH2-terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 fibroblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-deficient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.
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PMID:Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKS): evidence for a divergence of the ERKs and JNKs pathways induced by Ret. 962 10

Leukocyte adhesion to the extracellular matrix (ECM) is tightly controlled and is vital for the immune response. Circulating lymphocytes leave the bloodstream and adhere to ECM components at sites of inflammation and lymphoid tissues. Mechanisms for regulating T-lymphocyte-ECM adhesion include (i) an alteration in the affinity of cell surface integrin receptors for their extracellular ligands and (ii) an alteration of events following postreceptor occupancy (e.g., cell spreading). Whereas H-Ras and R-Ras were previously shown to affect T-cell adhesion by altering the affinity state of the integrin receptors, no signaling molecule has been identified for the second mechanism. In this study, we demonstrated that expression of an activated mutant of Rac triggered dramatic spreading of T cells and their increased adhesion on immobilized fibronectin in an integrin-dependent manner. This effect was not mimicked by expression of activated mutant forms of Rho, Cdc42, H-Ras, or ARF6, indicating the unique role of Rac in this event. The Rac-induced spreading was accompanied by specific cytoskeletal rearrangements. Also, a clustering of integrins at sites of cell adhesion and at the peripheral edges of spread cells was observed. We demonstrate that expression of RacV12 did not alter the level of expression of cell surface integrins or the affinity state of the integrin receptors. Moreover, our results indicate that Rac plays a role in the regulation of T-cell adhesion by a mechanism involving cell spreading, rather than by altering the level of expression or the affinity of the integrin receptors. Furthermore, we show that the Rac-mediated signaling pathway leading to spreading of T lymphocytes did not require activation of c-Jun kinase, serum response factor, or pp70(S6 kinase) but appeared to involve a phospholipid kinase.
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PMID:Rac regulates integrin-mediated spreading and increased adhesion of T lymphocytes. 963 78


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