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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In GN4 rat liver epithelial cells, angiotensin II (Ang II) produces intracellular calcium and protein kinase C (PKC) signals and stimulates ERK and JNK activity. JNK activation appears to be mediated by a calcium-dependent tyrosine kinase (CADTK). To define the ERK pathway, we established GN4 cells expressing an inhibitory Ras(N17). Induction of Ras(N17) blocked EGF- but not Ang II- or phorbol ester (TPA)-dependent ERK activation. In control cells, Ang II and TPA produced minimal increases in Ras-GTP level and Raf kinase activity. PKC depletion by chronic TPA exposure abolished TPA-dependent ERK activation but failed to diminish the effect of Ang II. In PKC-depleted cells, Ang II increased Ras-GTP level and activated Raf and ERK in a Ras-dependent manner. In PKC depleted cells, Ang II stimulated Shc and Cbl tyrosine phosphorylation, suggesting that without PKC, Ang II activates another tyrosine kinase. PKC-depletion did not alter Ang II-dependent tyrosine phosphorylation or activity of p125(FAK), CADTK, Fyn or Src, but PKC depletion or incubation with GF109203X resulted in Ang II-dependent EGF receptor tyrosine phosphorylation. In PKC-depleted cells, EGF receptor-specific tyrosine kinase inhibitors blocked Ang II-dependent EGF receptor and Cbl tyrosine phosphorylation, and ERK activation. In summary, Ang II can activate ERK via two pathways; the latent EGF receptor, Ras-dependent pathway is equipotent to the Ras-independent pathway, but is masked by PKC action. The prominence of this G-protein coupled receptor to EGF receptor pathway may vary between cell types depending upon modifiers such as PKC.
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PMID:Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway. 956 40

We cloned the cDNA for human RGSZ1, the major Gz-selective GTPase-activating protein (GAP) in brain (Wang, J., Tu, Y., Woodson, J., Song, X., and Ross, E. M. (1997) J. Biol. Chem. 272, 5732-5740) and a member of the RGS family of G protein GAPs. Its sequence is 83% identical to RET-RGS1 (except its N-terminal extension) and 56% identical to GAIP. Purified, recombinant RGSZ1, RET-RGS1, and GAIP each accelerated the hydrolysis of Galphaz-GTP over 400-fold with Km values of approximately 2 nM. RGSZ1 was 100-fold selective for Galphaz over Galphai, unusually specific among RGS proteins. Other enzymological properties of RGSZ1, brain Gz GAP, and RET-RGS1 were identical; GAIP differed only in Mg2+ dependence and in its slightly lower selectivity for Galphaz. RGSZ1, RET-RGS1, and GAIP thus define a subfamily of Gz GAPs within the RGS proteins. RGSZ1 has no obvious membrane-spanning region but is tightly membrane-bound in brain. Its regulatory activity in membranes depends on stable bilayer association. When co-reconstituted into phospholipid vesicles with Gz and m2 muscarinic receptors, RGSZ1 increased agonist-stimulated GTPase >15-fold with EC50 <12 nM, but RGSZ1 added to the vesicle suspension was <0.1% as active. RGSZ1, RET-RGS1, and GAIP share a cysteine string sequence, perhaps targeting them to secretory vesicles and allowing them to participate in the proposed control of secretion by Gz. Phosphorylation of Galphaz by protein kinase C inhibited the GAP activity of RGSZ1 and other RGS proteins, providing a mechanism for potentiation of Gz signaling by protein kinase C.
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PMID:RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily. 974 80

The B cell antigen receptor (BCR) activates Ras, a GTPase that promotes cell proliferation by activating the Raf-1/MEK/ERK signaling module and other signaling enzymes. In its active GTP-bound form, the Rap1 GTPase may act as a negative regulator of Ras-mediated signaling by sequestering Ras effectors (e.g., Raf-1) and preventing their activation. In this report, we show that BCR engagement activates Rap1 and that this is dependent on production of diacylglycerol (DAG) by phospholipase C-gamma. Activation of Rap1 by the BCR was greatly reduced in phospholipase C-gamma-deficient B cells, whereas both a synthetic DAG and phorbol dibutyrate could activate Rap1 in B cells. We had previously shown that C3G, an activator of Rap1, associates with the Crk adaptor proteins in B cells and that BCR engagement causes Crk to bind to the Cas and Cbl docking proteins. However, the DAG-dependent pathway by which the BCR activates Rap1 apparently does not involve Crk signaling complexes since phorbol dibutyrate could activate Rap1 without inducing the formation of these complexes. Thus, the BCR activates Rap1 via a novel DAG-dependent pathway.
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PMID:Activation of the Rap1 GTPase by the B cell antigen receptor. 978 33

TC21 is a member of the Ras superfamily of small GTP-binding proteins and, like Ras, has been implicated in the regulation of growth-stimulating pathways. Point mutations introduced into TC21 based on equivalent H-Ras oncogenic mutations are transforming in cultured cells, and oncogenic mutations in TC21 have been isolated from several human tumours. The mechanism of TC21 signalling in transformation is poorly understood. While activation of the serine/threonine kinases Raf-1 and B-Raf has been implicated in signalling pathways leading to transformation by H-Ras, it has been argued that TC21 does not activate Raf-1 or B-Raf. Since the Raf-signalling pathway is important in transformation by other Ras proteins, we assessed whether the Raf pathway is important to transformation by TC21. Raf-1 and B-Raf are constitutively active in TC21-transformed cells and the ERK/MAPK cascade is required for the maintenance of the transformed state. We demonstrate that oncogenic V23 TC21, like Ras, interacts with Raf-1 and B-Raf (but not with A-Raf), resulting in the translocation of the Raf proteins to the plasma membrane and in their activation. Furthermore, using point mutations in the effector loop of TC21, we show that the interaction of TC21 with Raf-1 is crucial for transformation.
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PMID:Activation of the Raf/MAP kinase cascade by the Ras-related protein TC21 is required for the TC21-mediated transformation of NIH 3T3 cells. 1006 93

M-Ras is a Ras-related protein that shares approximately 55% identity with K-Ras and TC21. The M-Ras message was widely expressed but was most predominant in ovary and brain. Similarly to Ha-Ras, expression of mutationally activated M-Ras in NIH 3T3 mouse fibroblasts or C2 myoblasts resulted in cellular transformation or inhibition of differentiation, respectively. M-Ras only weakly activated extracellular signal-regulated kinase 2 (ERK2), but it cooperated with Raf, Rac, and Rho to induce transforming foci in NIH 3T3 cells, suggesting that M-Ras signaled via alternate pathways to these effectors. Although the mitogen-activated protein kinase/ERK kinase inhibitor, PD98059, blocked M-Ras-induced transformation, M-Ras was more effective than an activated mitogen-activated protein kinase/ERK kinase mutant at inducing focus formation. These data indicate that multiple pathways must contribute to M-Ras-induced transformation. M-Ras interacted poorly in a yeast two-hybrid assay with multiple Ras effectors, including c-Raf-1, A-Raf, B-Raf, phosphoinositol-3 kinase delta, RalGDS, and Rin1. Although M-Ras coimmunoprecipitated with AF6, a putative regulator of cell junction formation, overexpression of AF6 did not contribute to fibroblast transformation, suggesting the possibility of novel effector proteins. The M-Ras GTP/GDP cycle was sensitive to the Ras GEFs, Sos1, and GRF1 and to p120 Ras GAP. Together, these findings suggest that while M-Ras is regulated by similar upstream stimuli to Ha-Ras, novel targets may be responsible for its effects on cellular transformation and differentiation.
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PMID:M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. 1044 49

T cell stimulation leads to triggering of signals transmitted from the cell membrane to the nucleus through TCR/CD3 proteins. Characterization of these signals largely results from the use of cell lines stimulated with anti-CD3 monoclonal antibodies. These studies have established that activation caused a rapid increase in the formation of GTP-bound Ras, which stimulates the mitogen-activated protein kinase pathway involving the extracellular-regulated kinase-2 (ERK-2) and activates the nuclear factor of activated T cells (NF-AT) that regulates interleukin-2 (IL-2) gene transcription. In the present study, we used human primary T cells, and we investigated the intracellular signals triggered by two different anti-CD3 monoclonal antibodies (UCHT1 and X-35), which both strongly induce cell proliferation. We found that, in contrast to the commonly used UCHT1, X-35 activated IL-2 gene transcription without stimulation of the Raf-1/mitogen-activated ERK kinase-1 (MEK-1)/ERK-2 phosphorylation cascade; we also showed that X-35 stimulation, which triggers an ERK-2-independent pathway, does not involve activation of p21(ras). In addition to demonstrating that activation of p21(ras) and of its Raf-1/MEK-1/ERK-2 effector pathway is not an event obligatorily triggered upon TCR/CD3 ligation, these results provide the first evidence of the existence of a p21(ras)/ERK-2-independent pathway for IL-2 gene transcription in human primary T lymphocytes.
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PMID:Evidence for a p21(ras)/Raf-1/MEK-1/ERK-2-independent pathway in stimulation of IL-2 gene transcription in human primary T lymphocytes. 1046 12

Many receptors for neuropeptides and hormones are coupled with the heterotrimeric G(i) protein, which activates the p42/44 mitogen-activated protein kinase (ERK/MAPK) cascade through both the alpha- and betagamma-subunits of G(i). The betagamma-subunit activates the ERK/MAPK cascade through tyrosine kinase. Constitutively active G(alpha)i2 (gip2) isolated from adrenal and ovarian tumours transforms Rat-1 fibroblasts and also activates the ERK/MAPK cascade by an unknown mechanism. The ERK/MAPK pathway is activated by Ras, and is inhibited when the low-molecular-mass GTP-binding protein Rap1 antagonizes Ras function. Here we show that a novel isoform of Rapl GTPase-activating protein, called rap1GAPII, binds specifically to the alpha-subunits of the G(i) family of heterotrimeric G-proteins. Stimulation of the G(i)-coupled m2-muscarinic receptor translocates rap1GAPII from the cytosol to the membrane and decreases the amount of GTP-bound Rap1. This decrease in GTP-bound Rap1 activates ERK/MAPK. Thus, the alpha-subunit of G(i) activates the Ras-ERK/MAPK mitogenic pathway by membrane recruitment of rap1GAPII and reduction of GTP-bound Rap1.
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PMID:Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i) 1047 55

In an attempt to gain insight into the molecular mechanisms involved in interleukin-9 (IL-9) activities, representational difference analysis (RDA) was used to identify messages that are induced by IL-9 in a murine T-helper-cell clone. One of the isolated genes encodes for the newly described M-Ras or R-Ras3, which is part of the Ras gene superfamily. M-Ras expression was found to be induced by IL-9 but not IL-2 or IL-4 in various murine T-helper-cell clones, and this induction seems to be dependent on the JAK/STAT pathway. Contrasting with the potent upregulation of M-Ras expression, M-Ras was not activated by IL-9 at the level of guanosine triphosphate/guanosine diphosphate (GTP/GDP) binding. However, IL-3 increased GTP binding to M-Ras, suggesting that M-Ras induction might represent a new mechanism of cooperativity between cytokines such as IL-3 and IL-9. Constitutively activated M-Ras mutants induced activation of Elk transcription factor by triggering the MAP kinase pathway and allowed for IL-3-independent proliferation of BaF3 cells. Taken together, these results show that cytokines such as IL-9 can regulate the expression of a member of the RAS family possibly involved in growth-factor signal transduction.
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PMID:Interleukin-9-induced expression of M-Ras/R-Ras3 oncogene in T-helper clones. 1047 95

Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.
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PMID:Familial medullary thyroid carcinoma: presymptomatic diagnosis and management in children. 1048 98

The relationship between protein kinase C (PKC) activation and Ras function was investigated in cardiac cells. Ras function was required for ERK activation by phorbol esters in cardiac myocytes, but not in cardiac fibroblasts. Accordingly, treatment with phorbol esters resulted in GTP loading of Ras in cardiac myocytes, but not fibroblasts. Ras activation by phorbol esters was abolished by a PKC specific inhibitor, but was insensitive to tyrosine kinase inhibitors. Ras activation was mediated by stimulation of guanine nucleotide exchange. These results suggest the existence of a novel pathway for Ras activation, specific to cardiac myocytes, with implications for myocardial hypertrophy.
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PMID:Activation of Ras by phorbol esters in cardiac myocytes. Role of guanine nucleotide exchange factors. 1057 Oct 61


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