Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selenium, an essential biological trace element, is an integral component of several enzymes, and its use as a nutritional supplement has been popularized recently due to its potential role in low concentrations as an antioxidant and in higher concentrations as an anticancer agent. Selenium has also been reported to act as an insulin-mimetic agent with regard to normalization of blood glucose levels and regulation of some insulin-mediated metabolic processes. Little work, however, has been done concerning the pathway(s) by which this insulin-mimetic action occurs. In this study, we investigated the mechanism by which selenate exhibits insulin-mimetic properties in two different insulin responsive cell types, primary rat hepatocytes and 3T3 L1 adipocytes. We found that two proteins associated with the insulin signal cascade, the beta-subunit of the insulin receptor and IRS-1, increased in tyrosyl phosphorylation in the presence of selenium. The third identified selenium activated signal protein, MAP kinase, has been implicated not only in the insulin signal transduction pathway but also in other growth factor-mediated responses. Using an in-gel activity assay for MAP kinase, we demonstrated that both the p42 and p44 MAP kinases are activated when either hepatocytes or adipocytes are incubated in the presence of selenate. In addition to the activation of these specific proteins, we found that selenium also eventually profoundly affected overall tyrosyl phosphorylation. Our results therefore show that selenium not only increased the phosphorylation of proteins identified in the insulin signal cascade but also affected the overall phosphorylation state of the cell.
 ...
PMID:Selenium: potent stimulator of tyrosyl phosphorylation and activator of MAP kinase. 906 Sep 97

GH has long been known as a regulator of body growth and metabolism, yet its mechanism of action at the cellular level has been elusive. We have recently shown that GH promotes the rapid association of GH receptor with the tyrosine kinase JAK2, activates JAK2, and promotes the tyrosyl phosphorylation of both JAK2 and GH receptor. This suggests that the initial signalling event in GH action is the activation of JAK2 which in turn phosphorylates tyrosines within JAK2 and GH receptor. We have identified a number of proteins that appear to bind to these phosphotyrosines in GH receptor/ JAK2 complexes. These proteins in turn become phosphorylated on tyrosines, resulting in their activation. These proteins include: 1) the signal transducers and activators of transcriptions (Stats) 1, 3 and 5 which have been implicated as regulators of transcription of a variety of genes; 2) the insulin receptor substrates (IRS) 1 and 2, which are believed to mediate some of the metabolic effects of GH; and 3) Shc proteins which lie upstream of Ras and the mitogen activator kinases (MAP) designated ERKs 1 and 2, proteins implicated in the regulation of cellular growth and/or differentiation. These various proteins work in concert with each other and with other signalling molecules to elicit the diverse effects of GH. Other hormones and growth factors also activate JAK kinases. Specificity in signalling was investigated by determining whether signalling pathways for particular ligands may be selectively inhibited by hormones or growth factors. Glucocorticoids were found to selectively decrease binding and cellular signalling in response to GH. This decrease appeared to be due to a decrease in the number of GH receptors in the plasma membrane. Using truncated and mutated GHR, two regions of the GH receptor were identified required for the inhibitory effect of glucocorticoids. Interestingly, they appeared to differ from the region required for GH-induced internalization. Hence, a large amount of insight into signalling by GH has been obtained during the 3 years since JAK2 was identified as a signalling molecule for GH and other ligands that bind to members of the cytokine receptor family. This new insight, and the insight that will continue to be gained in the next few years should enable the design of new and better therapeutic uses of GH and the other ligands that bind to JAK kinase-linked receptors.
 ...
PMID:Signalling pathway of GH. 907 44

The action of insulin and IGF-1 in comparison to non-diabetic controls was studied in cultured fibroblasts of a patient with an inherited syndrome of insulin resistance (Type A syndrome). Insulin binding was reduced due to decreased receptor affinity, but sequence analyses revealed no alterations of splicing or primary insulin receptor (IR) structure. Most likely due to the IR affinity defect analyses of signal transduction pathways showed an impairment of insulin action on glucose uptake, total RNA synthesis and phosphorylation as well as activity of MAP-kinase. In addition inducibility of c-fos mRNA level was strongly impaired by insulin and IGF-1, but comparable to controls by PDGF indicating a postreceptor defect. In conclusion, we provide evidence that genetic syndromes of insulin resistance can be associated with both, receptor and postreceptor defects.
 ...
PMID:Defects of insulin and IGF-1 action at receptor and postreceptor level in a patient with type A syndrome of insulin resistance. 917 64

To address whether Ras can be activated by insulin in the PC12 cell line, proteins interacting with insulin receptor and IRS-1 molecules and their tyrosine phosphorylation were analyzed by immunoblotting following immunoprecipitation with antibodies. Tyrosine phosphorylation of the insulin receptor and IRS-1 was increased by insulin. Grb2 and Ras-GAP appeared in the immunoprecipitates by anti-insulin receptor and anti-IRS-1 from insulin-treated cells. In addition, PI 3-kinase was activated by insulin treatment in this cell line and Grb2, Ras-GAP, and MAP kinase were coprecipitated with Ras from both insulin-treated and NGF-treated cells. Analysis of MAP kinases from insulin-treated cells revealed that insulin, like NGF, increased tyrosine phosphorylation. However, activation of the MAP kinase by NGF lasted longer than activation by insulin. These results indicate that Ras can be activated by insulin in the PC12 cell line and that Ras activation is neither an accurate nor a plausible method of discriminating signals between proliferation and differentiation.
 ...
PMID:Insulin activates Ras in the PC12 cell line. 926 35

The binding of insulin to its receptor initiates multiple signal transduction pathways regulating such diverse processes as proliferation, differentiation, glucose transport, and glycogen metabolism. The STAT-family of transcription factors has been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones. Furthermore, constitutive activation of STATs is observed in transformed cells. Here we describe activation of a transcriptional complex binding to a consensus STAT-transcriptional element in response to insulin challenge. This complex is induced rapidly after tyrosine autophosphorylation of the insulin receptor, and is sustained for several hours. Supershift analysis of the insulin-induced complex reveals that it specifically contains the transcription factor Stat3. DAN binding of this complex is inhibited by pre-incubation with tyrosine, but not serine/threonine protein kinase inhibitors, whereas transcriptional activation is inhibited by both. Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras. Furthermore, although previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT activation, utilising the specific MEK inhibitor PD098059 and the PI-3K inhibitor wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for insulin induced Stat3 phosphorylation or transactivation.
 ...
PMID:Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction. 939 41

In many human breast cancers and cultured cell lines, insulin receptor expression is elevated, and insulin, via its own insulin receptor, can stimulate cell growth. It has recently been demonstrated that the enzyme phosphatidylinositol-3-kinase (PI3-K) mediates various aspects of insulin receptor signaling including cell growth. In order to understand the mechanisms for insulin-stimulated cell growth in human breast cancer, we measured insulin-stimulable PI3-K activity in a non-transformed breast epithelial cell line, MCF-10A, and in two malignantly transformed cell lines, ZR-75-1 and MDA-MB157. All three cell lines express comparable amounts of insulin receptors whose tyrosine autophosphorylation is increased by insulin, and in these cell lines insulin stimulates growth. In MDA-MB157 and MCF-10A cells, insulin stimulated PI3-K activity three- to fourfold. In ZR-75-1 cells, however, insulin did not stimulate PI3-K activity. In ZR-75-1 cells PI3-K protein was present, and its activity was stimulated by epidermal growth factor, suggesting that there might be a defect in insulin receptor signaling upstream of PI3-K and downstream of the insulin receptor. Next, we studied insulin receptor substrate-1 (IRS-1), a major endogenous substrate for the insulin receptor which, when tyrosine is phosphorylated by the insulin receptor, interacts with and activates PI3-K. In ZR-75-1 cells, there were reduced levels of protein for IRS-1. In these cells, both Shc tyrosine phosphorylation and mitogen-activated protein kinase (MAP-K) activity were increased by the insulin receptor (indicating that the p21ras pathway may account for insulin-stimulated cell growth in ZR-75-1 cells). The PI3-K inhibitor LY294002 (50 microM) reduced insulin-stimulated growth in MCF-10A and MDA-MB157 cell lines, whereas it did not modify insulin effect on ZR-75-1 cell growth. The MAP-K/Erk (MEK) inhibitor PD98059 (50 microM) consistently reduced insulin-dependent growth in all three cell lines. Taken together, these data suggest that in breast cancer cells insulin may stimulate cell growth via PI3-K-dependent or-independent pathways.
 ...
PMID:Insulin-stimulated cell growth in insulin receptor substrate-1-deficient ZR-75-1 cells is mediated by a phosphatidylinositol-3-kinase-independent pathway. 967 Dec 32

Considerable progress has been made in our understanding of the molecular mechanisms of insulin action. The insulin receptor is a membrane receptor possessing tyrosine kinase activity. The binding of insulin to its receptor induces autophosphorylation of the receptor on tyrosine residues and thereby stimulates its tyrosine kinase activity towards intracellular substrates such as Shc or IRS1. This tyrosine kinase activity, which plays a crucial role in the transmission of the signal, is decreased in several insulin-resistance situations. This decrease was initially attributed to the phosphorylation of the receptor on serine or threonine residues, but this mechanism is now seriously questioned. Tyrosine phosphorylation of IRSs and Shc by the insulin receptor permits the activation of two major signalling pathways, the MAP kinase pathway and the Pl 3-kinase pathway. MAP kinases are involved in proliferation and differentiation processes, in particular by regulating the transcriptional activity of the nucleus. The MAP kinase pathway does not appear to play a significant role in the transmission of the metabolic effects of insulin. In contrast, the Pl 3-kinase pathway is involved in several of the metabolic effects of the hormone, such as glucose transport, glycolysis and glycogen synthesis. The Pl 3-kinase pathway also plays a crucial role in the regulation of protein synthesis by insulin. Moreover, this pathway is involved in cell growth and transmits a strong anti-apoptotic signal.
 ...
PMID:Molecular basis of insulin action. 993 14

The effect of insulin on glucose transport, glucose transporter 4 (Glut4) translocation, and intracellular signaling were measured in fat cells from lean and obese Zucker rats of different ages. Insulin-stimulated glucose transport was markedly reduced in adipocytes from old and obese animals. The protein content of Glut4 and insulin receptor substrates (IRS) 1 and 2 were also reduced while other proteins, including the p85 subunit of PI3-kinase, Shc and the MAP kinases (ERK1 and 2) were essentially unchanged. There was a marked impairment in the insulin stimulated tyrosine phosphorylation of IRS-1 and 2 as well as activation of PI3-kinase and PKB in cells from old and obese animals. Furthermore, insulin-stimulated translocation of both Glut4 and PKB to the plasma membrane was virtually abolished. The phosphotyrosine phosphatase inhibitor, vanadate, increased the insulin-stimulated upstream signaling including PI3-kinase and PKB activities as well as rate of glucose transport. Thus, the insulin resistance in cells from old and obese Zucker rats can be accounted for by an impaired translocation process, due to signaling defects leading to a reduced activation of PI3-kinase and PKB, as well as an attenuated Glut4 protein content.
 ...
PMID:Insulin resistance in fat cells from obese Zucker rats--evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4. 1083 89

In the present study we have examined the proteins involved in the insulin signaling cascade during and after differentiation of human adipocyte precursor cells and their correlation with glucose uptake. The differentiation of human adipocytes was characterized by a two- to threefold stimulation of glucose transport in response to insulin and a marked increase protein expression for the insulin receptor, IRS-1, GLUT-4, PI 3-kinase, and PKB, with respect to undifferentiated cells. In contrast, there were small changes in the protein expression of IRS-2, and no changes in PKC zeta and MAP kinases, although basal MAP kinase activity and GLUT-1 protein were reduced during differentiation. In conclusion, there are quantitative differences in the regulation of IRS-1 and other proteins during differentiation which may contribute to more efficient insulin signaling leading to glucose uptake in mature fat cells. Alterations in this pattern may reflect or contribute to an insulin-resistant state.
 ...
PMID:Regulation of proteins involved in insulin signaling pathways in differentiating human adipocytes. 1100

There have been few studies on the specific signaling pathways involved in the transformation of epithelial cells by oncogenic protein tyrosine kinases. Here we investigate the requirement of MAP (MAPK) and phosphatidylinositol 3- (PI3K) kinases in the transformation of rat intestinal epithelial (RIE) cells by oncogenic forms of insulin receptor (gag-IR), insulin-like growth factor-1 receptor (gag-IGFR), and v-Src. MAPK is not significantly activated in cells transformed by gag-IR and gag-IGFR but is activated in v-Src transformed cells. Treatment with PD98059, a MEK inhibitor, at concentrations where MAPK activity was reduced below the basal level showed that MAPK is partially required for the monolayer growth of parental and transformed RIE cells. However, MAPK is not essential for the focus forming ability of the three oncogene-transformed cells. It is also not necessary for the colony forming ability of gag-IR- and gag-IGFR-, but is partially required for v-Src-transformed cells. PI3K is significantly activated in all three oncogene transformed RIE cells. LY294002, a PI3K inhibitor, potently inhibited monolayer growth of all three oncogene-transformed cells. However, at concentrations of LY294002 where activated forms of Akt, a downstream component of the PI3K pathway, were undetectable, colony and focus forming abilities of the v-Src-RIE cells were only slightly affected whereas those of gag-IR/IGFR-RIE cells were greatly inhibited. These results were confirmed using a different pharmacological inhibitor, wortmannin, and a dominant negative form of PI3K, Ap85. Similarly, rapamycin, known to inhibit p70S6 kinase, a downstream component of the PI3K-Akt pathway, also inhibited gag-IR/IGFR-induced, but not v-Src-induced, focus and colony formation. We conclude that the MAPK and PI3K signaling pathways are differentially required for transformation of RIE cells by oncogenic IR and IGFR versus Src and the pattern of requirements is different from that of fibroblast transformation.
 ...
PMID:Differential requirements of the MAP kinase and PI3 kinase signaling pathways in Src- versus insulin and IGF-1 receptors-induced growth and transformation of rat intestinal epithelial cells. 1110 40


<< Previous 1 2 3 4 Next >>