Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine phosphatases PTP-SL and PTPBR7 are isoforms belonging to cytosolic membrane-associated and to receptor-like PTPs (RPTPs), respectively. They represent a new family of PTPs with a major role in activation and translocation of MAP kinases. Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. This interaction is strictly dependent upon a kinase interaction motif (KIM) (residues 224-239) situated at the N terminus of the PTP-SL catalytic domain. We report the first crystal structure of the catalytic domain for a member of this family (PTP-SL, residues 254-549, identical with residues 361-656 of PTPBR7), providing an example of an RPTP with single cytoplasmic domain, which is monomeric, having an unhindered catalytic site. In addition to the characteristic PTP-core structure, PTP-SL has an N-terminal helix, possibly orienting the KIM motif upon interaction with the target ERK2. An unusual residue in the catalytically important WPD loop promotes formation of a hydrophobically and electrostatically stabilised clamp. This could induce increased rigidity to the WPD loop and therefore reduced catalytic activity, in agreement with our kinetic measurements. A docking model based on the PTP-SL structure suggests that, in the complex with ERK2, the phosphorylation of PTP-SL should be accomplished first. The subsequent dephosphorylation of ERK2 seems to be possible only if a conformational rearrangement of the two interacting partners takes place.
J Mol Biol 2001 Aug 17
PMID:Crystal structure of PTP-SL/PTPBR7 catalytic domain: implications for MAP kinase regulation. 1149 9

Bcl-2 has been reported to inhibit neurotoxicity induced by cisplatin. However, neither the mechanism of cisplatin-induced neurotoxicity nor the mechanism by which Bcl-2 confers neuroprotection is clear. In this study, the signaling pathways involved in cisplatin-induced neurotoxicity were examined using a rat neuroblastoma cell line, B104. Treatment of B104 cells with cisplatin induced apoptosis, accompanying the accumulation of p53 and Bax protein. Interestingly, extracellular signal-regulated kinase 1/2 (ERK1/2) activities of MAP kinases were markedly enhanced prior to cisplatin-induced accumulation of p53 and Bax. Inhibition of ERK1/2 activities using PD98059, a selective MEK inhibitor, blocked the apoptotic cell death preventing cisplatin-induced accumulation of p53 and Bax. These results suggest that ERK mediates cisplatin-induced p53 activation to trigger apoptosis in B104 cells. Overexpression of Bcl-2 in B104 cells resulted in the complete resistance to cisplatin-induced apoptosis blocking ERK activation and the subsequent signaling pathway of p53. Our study clearly demonstrates that the action site of Bcl-2 localizes upstream of ERK in cisplatin-induced apoptotic signaling pathway.
Brain Res Mol Brain Res 2001 Sep 10
PMID:Bcl-2 blocks cisplatin-induced apoptosis by suppression of ERK-mediated p53 accumulation in B104 cells. 1153 34

Signals transmitted by common components often elicit distinct (yet appropriate) outcomes. In yeast, two developmental options-mating and invasive growth-are both regulated by the same MAP kinase cascade. Specificity has been thought to result from specialized roles for the two MAP kinases, Kss1 and Fus3, and because Fus3 prevents Kss1 from gaining access to the mating pathway. Kss1 has been thought to participate in mating only when Fus3 is absent. Instead, we show that Kss1 is rapidly phosphorylated and potently activated by mating pheromone in wild-type cells, and that this is required for normal pheromone-induced gene expression. Signal identity is apparently maintained because active Fus3 limits the extent of Kss1 activation, thereby preventing inappropriate signal crossover.
Mol Cell 2001 Sep
PMID:Specificity of MAP kinase signaling in yeast differentiation involves transient versus sustained MAPK activation. 1158 29

We recently demonstrated that ischemic preconditioning (IPC) induced by cyclic episodes of short durations of ischemia and reperfusion potentiates a signal transduction cascade involving protein tyrosine kinases and MAP kinases. A rapid activation of janus kinase (JAK) and several signal transducers and activators of the transcription (STATs) including STAT3, STAT5A and STAT6 has been shown to occur during myocardial ischemia and reperfusion. This study sought to examine if JAK/STAT signaling pathway play any role in classical early phase of IPC. Isolated working rat hearts were perfused for 15 min with KHB buffer in the absence or presence of a JAK kinase inhibitor tyrphostin AG490 (5 microm) followed by IPC, 30 min global ischemia and 2 h of reperfusion. The results demonstrated extensive phosphorylation of JAK2 and STAT3 in the IPC hearts which was almost completely abolished by an inhibitor of JAK2, AG490. IPC displayed cardioprotection as evidenced by improved post-ischemic contractile recovery, decreased myocardial infarct size and reduced number of apoptotic cardiomyocytes. AG490 blocked IPC-mediated cardioprotection by altering the IPC-mediated survival signal into death signal. Thus, IPC-induced upregulation of antiapoptotic gene bcl-2 and downregulation of pro-apoptotic gene bax are decreased and increased, respectively, in the AG490 treated hearts. The results suggest that early phase of IPC potentiates JAK/STAT signaling by activating STAT3 which transmits a survival signal to the myocardium.
J Mol Cell Cardiol 2001 Nov
PMID:Role of STAT3 in ischemic preconditioning. 1170 38

In this issue of Molecular Cell, Stefanovsky et al. demonstrate that the activation of the ERK1/2 MAP kinases by growth factors leads to induction of ribosomal gene transcription, through a mechanism dependent on phosphorylation of the upstream binding factor (UBF). This provides a connection between growth factor signaling and increased translation.
Mol Cell 2001 Nov
PMID:ERKs weigh in on ribosome mass. 1174 41

The activation of growth factor receptors induces phosphorylation of tyrosine residues in its C-terminal part, creating binding sites for SH2 domain-containing proteins. Grb2 is a protein that recruits Sos, the exchange factor for Ras. Recruitment of Sos allows for Ras activation and subsequent signal transmission. This promotes translocation of MAP kinases into the nucleus and activation of early transcription factors. Grb2, a 25 kDa protein, is composed of one SH2 domain surrounded by two SH3 domains. The SH2 domain of Grb2 binds to class II phosphotyrosyl peptides with the consensus sequence pYXNX. Thus, Grb2 is a good example of a bifunctional adaptor protein that brings proteins into close proximity, allowing signal transduction through proteins located in different compartments. To explore the interactions between Grb2 and phosphorylated ligands, we have solved the crystal structure of complexes between the Grb2-SH2 domain and peptides corresponding to Shc-derived sequences. Two structures are described: the Grb2-SH2 domain in complex with PSpYVNVQN at 1.5 A; and the Grb2-SH2 domain in complex with mAZ*-pY-(alphaMe)pY-N-NH2 pseudo-peptide, at 2 A. Both are compared to an unliganded SH2 structure determined at 2.7 A which, interestingly enough, forms a dimer through two swapping subdomains from two symmetry-related molecules. The nanomolar affinity of the mAZ-pY-(alphaMe)pY-N-NH2 pseudo-peptide for Grb2-SH2 is related to new interactions with non- conserved residues. The design of Grb2-SH2 domain inhibitors that prevent interaction with tyrosine kinase proteins or other adaptors like Shc or IRS1 should provide a means to interrupt the Ras signaling pathway. Newly synthesized pseudo-peptides exhibit nanomolar affinities for the Grb2-SH2 domain. It will then be possible to design new inhibitors with similar affinity and simpler chemical structures.
J Mol Biol 2002 Feb 01
PMID:Crystal structures of the SH2 domain of Grb2: highlight on the binding of a new high-affinity inhibitor. 1182 84

Cortical spreading depression (CSD) has been shown to have neuroprotective effects when administered in advance of cerebral ischemia. The mechanism by which CSD induces its neuroprotective effect however remains to be elucidated. Since MAP kinases have been shown to impart neuroprotection in ischemic preconditioning paradigms, we attempted to determine the role CSD may have in the activation of MAPK. We show that CSD is capable of increasing the phosphorylation of ERK in a MEK-dependent manner. This phosphorylation is, however, transient, as phosphorylated ERK levels return to control levels 45 min after 2 h of CSD elicitation. Immunohistochemical analysis reveals that the phosphorylated form of ERK is located ubiquitously in cells of the CSD-treated cortex while CSD-elicited MEK phosphorylation resides solely in the nuclei. These data suggest that CSD may act via the MAP kinase pathways to mediate preconditioning.
Brain Res Mol Brain Res 2002 Feb 28
PMID:Cortical spreading depression transiently activates MAP kinases. 1186 11

The biological and biochemical effects of estrogen have been ascribed to its known receptors, which function as ligand-inducible transcription factors. However, estrogen also triggers rapid activation of classical second messengers (cAMP, calcium, and inositol triphosphate) and stimulation of intracellular signaling cascades mitogen-activated protein kinase (MAP K), PI3K and eNOS. These latter events are commonly activated by membrane receptors that either possess intrinsic tyrosine kinase activity or couple to heterotrimeric G-proteins. We have shown that estrogen transactivates the epidermal growth factor receptor (EGFR) to MAP K signaling axis via the G-protein-coupled receptor (GPCR), GPR30, through the release of surface-bound proHB-EGF from estrogen receptor (ER)-negative human breast cancer cells [Molecular Endocrinology 14 (2000) 1649]. This finding is consistent with a growing body of evidence suggesting that transactivation of EGFRs by GPCRs is a recurrent theme in cell signaling. GPCR-mediated transactivation of EGFRs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the EGF-like effects of estrogen. This novel mechanism by which estrogen activates growth factor-dependent signaling and its implications for breast cancer biology are discussed further in this review.
J Steroid Biochem Mol Biol 2002 Feb
PMID:Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer. 1189 6

The role and regulation of signal transduction pathways in proliferation and differentiation of intestinal epithelial cells are still poorly understood. However, growing evidences have been recently accumulated demonstrating that mitogen-activated protein kinases (MAPKs) play a pivotal function in the normal development of intestine. We have investigated, in the intestinal cell line HT-29, the regulation (namely activity and phosphorylation degree) of MAP kinases ERK 1 (p44) and ERK 2 (p42) during differentiation. Addition of fetal calf serum to HT-29 undifferentiated resting cells caused a rapid phosphorylation of both ERKs and an increase of their specific kinase activity. Moreover, nuclear translocation of ERK 1 and ERK 2 occurred concurrently to their activation, leading to the conclusion that ERK 1 and ERK 2 are classically regulated when quiescent HT-29 cells are induced to proliferate. Butyrate addition to the intestinal cell line resulted in terminal differentiation and in a selective down-regulation of ERK 2 activity (and phosphorylation degree) without any effect on ERK 1. Conversely, when HT-29 cells were differentiated by repeated passages in a glucose-free medium, we observed a progressive dephosphorylation and inactivation of p42 and p44 kinases along with the failure of serum to activate both the enzymes. Our findings suggest that, during the differentiation of intestinal cells, remarkable changes occur in ERK 1 and ERK 2 control mechanisms leading to an unresponsiveness of MAP kinase pathway.
Mol Cell Biochem 2002 Feb
PMID:Down-regulation of ERK1 and ERK2 activity during differentiation of the intestinal cell line HT-29. 1195 64

Adhesion molecules and chemokines contribute to selective eosinophil recruitment in allergic inflammation. In this study, we examined the effects of eotaxin-2, a CCR3-specific chemokine, on integrin-mediated eosinophil adhesion to vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), or both using a parallel plate flow system. Tissue culture plates were coated with various combinations of VCAM-1, ICAM-1, and/or eotaxin-2. Human eosinophils were infused at physiologic shear stress (0.5 dyn/cm(2)) for 10 min, and the numbers of attached eosinophils were monitored using video microscopy. Cells accumulated efficiently on VCAM-1 and even better on surfaces co-coated with VCAM-1 and ICAM-1, but poorly on surfaces coated with ICAM-1 or bovine serum albumin alone. When eotaxin-2 was co-immobilized with adhesion proteins, fewer cells adhered to VCAM-1 and more adhered to ICAM-1, whereas levels of attachment to VCAM-1 plus ICAM-1 showed no net change. However, experiments with adhesion molecule blocking monoclonal antibody showed that the contribution of ICAM-1-mediated adhesion was always greater if eotaxin-2 was present. Pretreatment of cells with a CCR3-blocking mAb, or PD98059, a MAP-kinase inhibitor, prevented the eotaxin-2-induced changes in eosinophil attachment. These data suggest that eotaxin-2, acting via MAP kinases, may facilitate eosinophil recruitment at sites of allergic inflammation by shifting their adhesion molecule usage away from VCAM-1-dominated to ICAM-1-dominated pathways.
Am J Respir Cell Mol Biol 2002 Jun
PMID:Eotaxin-2 alters eosinophil integrin function via mitogen-activated protein kinases. 1203 62


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