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

---

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

Among peripheral T-cell lymphomas (PTCL), the heterogeneous category of unspecified PTCL represents the most common subtype. Nevertheless, recurrent chromosomal translocations are unknown in this aggressive type of lymphoma. Here we describe a novel t(5;9)(q33;q22) in unspecified PTCL. Molecular analyses delineated the breakpoints to ITK and SYK resulting in a previously undescribed expression of the Syk tyrosine kinase by Itk. ITK-SYK transcripts were detected in five of 30 (17%) unspecified PTCL, but not in cases of angioimmunoblastic T-cell lymphoma (n=9) and anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma (n=7). In all five translocation-positive cases, the breakpoints were identical fusing the N-terminal pleckstrin homology domain and proline-rich region of ITK to the tyrosine kinase domain of SYK. Three of the five t(5;9)(q33;q22)+ unspecified PTCL shared a very similar histological pattern with predominant involvement of lymphoid follicles and the same CD3+CD5+CD4+bcl-6+CD10+ immunophenotype. These results demonstrate the presence of a recurrent t(5;9)(q33;q22) in a subset of unspecified PTCL, which may represent a novel distinct subgroup of PTCL.
...
PMID:Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. 1630 12

LIM and SH3 protein (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell migration. LASP-1 is an actin binding protein, which also interacts with the proline-rich domains of zyxin, a scaffolding protein required for cell movement and gene transcription. In the present work, we analyzed the effect of LASP-1 on different human breast cancer cell lines. Transfection with LASP-1-specific siRNA resulted in a reduced protein level of LASP-1 in BT-20 and MCF-7 cell lines. The siRNA-treated cells were arrested in G2/M phase of cell cycle, and proliferation of the tumor cells was suppressed by 30-50% corresponding to around 50% of the cells being transfected successfully as seen by immunofluorescence. In addition, tumor cells showed a 50% reduced migration after siRNA treatment, while overexpression of LASP-1 in non-tumor PTK-2 cells, which do not express endogenous LASP-1, resulted in a significant increase in cell motility. LASP-1 silencing is accompanied with a reduced binding of the of LASP-1 binding partner zyxin to focal contacts without changes in actin stress fiber organization as observed in immunofluorescence experiments. The data provide evidence for an essential role of LASP-1 in tumor cell growth and migration, possibly by influencing the localization of zyxin.
...
PMID:Silencing of LASP-1 influences zyxin localization, inhibits proliferation and reduces migration in breast cancer cells. 1643 Aug 83

Rin1 is a multifunctional protein containing several domains, including Ras binding and Rab5 GEF domains. The role of Rin1 in insulin receptor internalization and signaling was examined by expressing Rin1 and deletion mutants in cells utilizing a retrovirus system. Here, we show that insulin-receptor-mediated endocystosis and fluid phase insulin-stimulated endocytosis are enhanced in cells expressing the Rin1:wild type and the Rin1:C deletion mutant, which contain both the Rab5-GEF and GTP-bound Ras binding domains. However, the Rin1:N deletion mutant, which contains both the SH2 and proline-rich domains, blocked insulin-stimulated receptor-mediated and insulin-stimulated fluid phase endocytosis. In addition, the expression of Rin1:delta (429-490), a natural occurring splice variant, also blocked both receptor-mediated and fluid phase endocystosis. Furthermore, association of the Rin1 SH2 domain with the insulin receptor was dependent on tyrosine phosphorylation of the insulin receptor. Morphological analysis indicates that Rin1 co-localizes with insulin receptor both at the cell surface and in endosomes upon insulin stimulation. Interestingly, the expression of Rin1:wild type and both deletion mutants blocks the activation of Erk1/2 and Akt1 kinase activities without affecting either JN or p38 kinase activities. DNA synthesis and Elk-1 activation are also altered by the expression of Rin1:wild type and the Rin1:C deletion mutant. In contrast, the expression of Rin1:delta stimulates both Erk1/2 and Akt1 activation, DNA synthesis and Elk-1 activation. These results demonstrate that Rin1 plays an important role in both insulin receptor membrane trafficking and signaling.
...
PMID:Rin1 regulates insulin receptor signal transduction pathways. 1645 16

Both phospholipase (PL) C-gamma1 and Akt (protein kinase B; PKB) are signaling proteins that play significant roles in the intracellular signaling mechanism used by receptor tyrosine kinases, including epidermal growth factor (EGF) receptor (EGFR). EGFR activates PLC-gamma1 directly and activates Akt indirectly through phosphatidylinositol 3-kinase (PI3K). Many studies have shown that the PLC-gamma1 pathway and PI3K-Akt pathway interact with each other. However, it is not known whether PLC-gamma1 binds to Akt directly. In this communication, we identified a novel interaction between PLC-gamma1 and Akt. We demonstrated that the interaction is mediated by the binding of PLC-gamma1 Src homology (SH) 3 domain to Akt proline-rich motifs. We also provide a novel model to depict how the interaction between PLC-gamma1 SH3 domain and Akt proline-rich motifs is dependent on EGF stimulation. In this model, phosphorylation of PLC-gamma1 Y783 by EGF causes the conformational change of PLC-gamma1 to allow the interaction of its SH3 domain with Akt proline-rich motifs. Furthermore, we showed that the interaction between PLC-gamma1 and Akt resulted in the phosphorylation of PLC-gamma1 S1248 by Akt. Finally, we showed that the interaction between PLC-gamma1 and Akt enhanced EGF-stimulated cell motility.
...
PMID:Akt binds to and phosphorylates phospholipase C-gamma1 in response to epidermal growth factor. 1652 23

Because the Sprouty (Spry) proteins were shown to be inhibitors of the mainstream Ras/ERK pathway, there has been considerable interest in ascertaining their mechanism of action especially since a possible role as tumor suppressors for these inhibitory proteins has been suggested. We compared the ability of the mammalian Spry isoforms to inhibit the Ras/ERK pathway in the context of fibroblast growth factor receptor (FGFR) signaling. Spry2 is considerably more inhibitory than Spry1 or Spry4, and this correlates with the binding to Grb2 via a C-terminal proline-rich sequence that is found exclusively on Spry2. This PXXPXR motif binds directly to the N-terminal Src homology domain 3 of Grb2, and when added onto the C terminus of Spry4 the resultant chimera inhibits the Ras/ERK pathway. The ability to inhibit neurite outgrowth in PC-12 cells correlates with the propensity of Spry isoforms and engineered constructs to inhibit the phosphorylation of ERK1/2. The PXXPXR motif is cryptic in unstimulated cells, and it is postulated that Spry2 undergoes a conformational change following FGFR stimulation, enabling the subsequent interaction with Grb2. We present evidence that Spry2 can compete with the RasGEF (guanine nucleotide exchange factor) SOS1 for binding to Grb2, resulting in the inhibition of phosphorylation of ERK1/2.
...
PMID:A Src homology 3-binding sequence on the C terminus of Sprouty2 is necessary for inhibition of the Ras/ERK pathway downstream of fibroblast growth factor receptor stimulation. 1689 2

G protein-coupled receptors (GPCRs) such as angiotensin II, bradykinin and endothelin-1 (ET-1) are critically involved in the regulation of adrenal function, including aldosterone production from zona glomerulosa cells. Whereas, substantial data are available on the signaling mechanisms of ET-1 in cardiovascular tissues, such information in adrenal glomerulosa cells is lacking. Bovine adrenal glomerulosa (BAG) cells express receptors for endothelin-1 (ET-1) and their stimulation caused phosphorylation of Src (at Tyr416), proline-rich tyrosine kinase (Pyk2 at Tyr402), extracellularly regulated signal kinases (ERK1/2), and their dependent proteins, p90 ribosomal S6 kinase (RSK-1) and CREB. ET-1 elicited these responses predominantly through activation of a G(i)-linked cascade with a minor contribution from the G(q)/PKC pathway. Whereas, selective inhibition of EGF-R kinase with AG1478 caused complete inhibition of EGF-induced ERK/RSK-1/CREB activation, it caused only partial reduction (30-40%) of such ET-1-induced responses. Consistent with this, inhibition of matrix metalloproteinases (MMPs) with GM6001 reduced ERK1/2 activation by ET-1, consistent with partial involvement of the MMP-dependent EGF-R activation in this cascade. Activation of ERK/RSK-1/CREB by both ET-1 and EGF was abolished by inhibition of Src, indicating its central role in ET-1 signaling in BAG cells. Moreover, the signaling characteristics of ET-1 in cultured BAG cells closely resembled those observed in clonal adrenocortical H295R cells. The ET-1-induced proliferation of BAG and H295 R cells was much smaller than that induced by Ang II or FGF. These data demonstrate that ET-1 causes ERK/RSK-1/CREB phosphorylation predominantly through activation of G(i) and Src, with a minor contribution from MMP-dependent EGF-R transactivation.
...
PMID:Mechanisms of endothelin-1-induced MAP kinase activation in adrenal glomerulosa cells. 1711 76

The saimiri transforming protein oncogene, called STP-A, of herpesvirus saimiri (HVS) subgroup A is not required for viral replication but is required for lymphoid cell immortalization in culture and lymphoma induction in primates. Here we report that STP-A interacts with cellular tumor necrosis factor receptor-associated factors (TRAF2 and TRAF6) and Src family protein tyrosine kinases (SF-PTKs) in a genetically and functionally separable manner and that each interaction constitutively elicits independent cellular signal transduction. The amino-terminal and central proline-rich motifs of STP-A were responsible for TRAF6 and TRAF2 interactions, respectively, and STP-A and TRAF6 interaction contributed to the majority of NF-kappaB activation, whereas STP-A and TRAF2 interaction played a minor role in NF-kappaB activation. On the other hand, interaction of STP-A with SF-PTKs through its SH2 binding motif effectively elicited AP-1 and NF-AT transcription factor activity. One cellular gene targeted by STP-A is intercellular adhesion molecule 1 (ICAM-1), which participates in a wide range of inflammatory and immune responses. Both TRAF and SF-PTK signal transductions induced by STP-A were required for the marked increase of ICAM-1 expression. These results demonstrate that the viral oncogene STP-A independently targets two vital cellular signaling molecules and that these activities likely contribute to HVS-mediated lymphoid cell immortalization in culture and lymphoma induction in primates.
...
PMID:Herpesvirus saimiri STP-A oncoprotein utilizes Src family protein tyrosine kinase and tumor necrosis factor receptor-associated factors to elicit cellular signal transduction. 1718 73

The proapoptotic protein Bad is a key player in cell survival decisions, and is regulated post-translationally by several signaling networks. We expressed Bad in mouse embryonic fibroblasts to sensitize them to apoptosis, and tested cell lines derived from knock-out mice to establish the significance of the interaction between the adaptor protein Grb10 and the Raf-1 protein kinase in anti-apoptotic signaling pathways targeting Bad. When compared with wild-type cells, both Grb10 and Raf-1-deficient cells exhibit greatly enhanced sensitivity to apoptosis in response to Bad expression. Structure-function analysis demonstrates that, in this cellular model, the SH2, proline-rich, and pleckstrin homology domains of Grb10, as well as its Akt phosphorylation site and consequent binding by 14-3-3, are all necessary for its anti-apoptotic functions. As for Raf-1, its kinase activity, its ability to be phosphorylated by Src on Tyr-340/341 and the binding of its Ras-associated domain to the Grb10 SH2 domain are all necessary to promote cell survival. Silencing the expression of either Grb10 or Raf-1 by small interfering RNAs as well as mutagenesis of specific serine residues on Bad, coupled with signaling inhibitor studies, all indicate that Raf-1 and Grb10 are required for the ability of both the phosphatidylinositol 3-kinase/Akt and MAP kinase pathways to modulate the phosphorylation and inactivation of Bad. Because total Raf-1, ERK, and Akt kinase activities are not impaired in the absence of Grb10, we propose that this adapter protein creates a subpopulation of Raf-1 with specific anti-apoptotic activity.
...
PMID:Grb10 and active Raf-1 kinase promote Bad-dependent cell survival. 1753 12

PRAS40 binds to the mTORC1 (mammalian target of rapamycin complex 1) and is released in response to insulin. It has been suggested that this effect is due to 14-3-3 binding and leads to activation of mTORC1 signalling. In a similar manner to insulin, phorbol esters also activate mTORC1 signalling, in this case via PKC (protein kinase C) and ERK (extracellular-signal-regulated kinase). However, phorbol esters do not induce phosphorylation of PRAS40 at Thr(246), binding of 14-3-3 proteins to PRAS40 or its release from mTORC1. Mutation of Thr(246) to a serine residue permits phorbol esters to induce phosphorylation and binding to 14-3-3 proteins. Such phosphorylation is apparently mediated by RSKs (ribosomal S6 kinases), which lie downstream of ERK. However, although the PRAS40(T246S) mutant binds to 14-3-3 better than wild-type PRAS40, each inhibits mTORC1 signalling to a similar extent. Our results show that activation of mTORC1 signalling by phorbol esters does not require PRAS40 to be phosphorylated at Thr(246), bind to 14-3-3 or be released from mTORC1. It is conceivable that phorbol esters activate mTORC1 by a distinct mechanism not involving PRAS40. Indeed, our results suggest that PRAS40 may not actually be involved in controlling mTORC1, but rather be a downstream target of mTORC1 that is regulated in response only to specific stimuli, such as insulin.
...
PMID:The binding of PRAS40 to 14-3-3 proteins is not required for activation of mTORC1 signalling by phorbol esters/ERK. 1821 33

PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) is a novel estrogen receptor (ER)-interacting protein that has been implicated to be important for mediation of both the genomic and nongenomic signaling of 17beta-estradiol (E2). PELP1 contains ten nuclear receptor-interacting boxes (LXXLL motifs), which allow it to interact with ER and other nuclear hormone receptors, a zinc finger, a glutamic acid-rich domain, and two proline-rich domains. The proline-rich regions contain several consensus PXXP motifs, which allow PELP1 to couple the ER with SH3 domain-containing kinase signaling proteins, such as Src and PI3K P85 regulatory subunit. PELP1 is expressed in many different brain regions, including the hippocampus, hypothalamus, and cerebral cortex. Further work has demonstrated that PELP1 is colocalized with ER-alpha in neurons in various brain regions. PELP1 is primarily expressed in neurons, with some expression also observed in glia. Subcellular localization studies revealed that PELP1 is highly localized in the cell nucleus of neurons, with some cytoplasm localization as well, and PELP1 is also localized at synaptic sites. Work in other tissues has demonstrated that PELP1 is critical for nongenomic and genomic signaling by E2, as PELP1 knockdown studies significantly attenuates E2-induced activation of ERK and Akt signaling pathways, and inhibits E2 genomic transcriptional effects on gene expression in breast cancer cells. Preliminary studies in the brain, suggests that similar roles may exist for PELP1 in the brain, but this remains to be established, and further work to characterize the precise roles and functions of PELP1 in the brain are needed.
...
PMID:PELP1--a novel estrogen receptor-interacting protein. 1857 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---