Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-ret proto-oncogene encodes a receptor tyrosine kinase which plays an important role in kidney and enteric nervous system development. Germline mutations in c-ret are responsible for the dominantly inherited cancer syndromes, multiple endocrine neoplasia types 2A and 2B and familial medullary thyroid carcinoma as well as the developmental disorder Hirschsprung's disease. Using SK-N-MC neuroepithelioma cells stably transfected with an EGFR/Ret chimeric receptor, we have studied cellular consequences and signalling events following activation of exogenous EGFR/Ret and endogenous FGF and PDGF receptor tyrosine kinases in cells of neuroectodermal origin. Here we report that Ret activation led to cell scattering, growth inhibition and loss of anchorage-independent growth. Basic FGF, but not PDGF, evoked similar responses in those cells. Nevertheless, activation of all three receptor tyrosine kinases led to ERK2 activation. Analysis of the kinetics of ERK2 activation and downstream events revealed that Ret and FGF receptor activation led to sustained ERK2 activation and SRE transactivation, while PDGF treatment led to transient ERK2 activation and failed to induce SRE transactivation. Our results suggest that sustained, but not transient ERK2 activation may be involved in cell scattering.
 ...
PMID:Cell scattering of SK-N-MC neuroepithelioma cells in response to Ret and FGF receptor tyrosine kinase activation is correlated with sustained ERK2 activation. 912 63

Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.
 ...
PMID:Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase. 939 66

Cancer is a genetic disease caused by 'gain of function' mutations of oncogenes and 'loss of function' mutations of tumour suppressors and of genes involved in DNA repair mechanisms. The RET gene encodes a tyrosine kinase receptor for molecules belonging to the glial cell line-derived neurotrophic factor (GDNF) family. RET is a paradigmatic example of how different mutations of a single gene can lead to different neoplastic phenotypes. Indeed, gene rearrangements, often caused by chromosomal inversions, activate the oncogenic potential of RET in a fraction of human thyroid papillary carcinomas. On the other hand, different point mutations activate RET in familial multiple endocrine neoplasia syndromes familial medullary thyroid carcinoma (FMTC), MEN-2A and MEN-2B. Little information is so far available on the biochemical mechanisms by which the potent transforming and mitogenic signals of RET are delivered to the nucleus. However, recent data indicate coupling to the Shc-Ras-MAPK pathway as a necessary step in RET signal transduction.
 ...
PMID:Molecular biology of the MEN2 gene. 968 50

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the calcitonin secreting thyroid C-cells. Somatic and germline mutations in the RET proto-oncogene are associated with sporadic and inherited cases of MTC, respectively. The human MTC cell line, TT, can be differentiated by activated raf-1. This differentiation is characterized, in part, by down-regulation of the RET proto-oncogene. We now show that raf-1 induction is followed by activation of the downstream kinases MEK1/2 and ERK1/2 and that differentiation is dependent on activation of MEK1/2. The concurrent down-regulation of RET appears to involve altered nuclear compartmentalization and transport of RET mRNA. Although RET is down-regulated during raf-1 mediated differentiation, overexpression of activated RET alleles which resist down-regulation does not alter the raf-1 mediated differentiation response. These data suggest that RET down-regulation is associated with, but not required, for raf-1 mediated MTC cell differentiation and that the raf-1 signal transduction pathway plays a dominant role in promoting MTC cell differentiation.
 ...
PMID:Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells. 969 May 18

Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant syndrome characterized by the development of medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies and mucosal ganglioneuromas. MEN2B is caused by a specific mutation (Met918-->Thr) in the RET receptor tyrosine kinase. Different mutations of RET lead to other conditions including MEN2A, familial medullary thyroid carcinoma and intestinal aganglionosis (Hirschsprung disease). Transgenic mice were created using the dopamine beta-hydroxylase promoter to direct expression of RET(MEN2B) in the developing sympathetic and enteric nervous systems and the adrenal medulla. DbetaH-RET(MEN2B) transgenic mice developed benign neuroglial tumors, histologically identical to human ganglioneuromas, in their sympathetic nervous systems and adrenal glands. The enteric nervous system was not affected. The neoplasms in DbetaH-RET(MEN2B) mice were similar to benign neuroglial tumors induced in transgenic mice by activated Ras expression under control of the same promoter. Levels of phosphorylated MAP kinase were not increased in the RET(MEN2B)-induced neurolglial proliferations, suggesting that alternative pathways may play a role in the pathogenesis of these lesions. Transgenic mice with the highest levels of DbetaH-RET(MEN2B) expression, unexpectedly developed renal malformations analogous to those reported with loss of function mutations in the Ret gene.
 ...
PMID:Ganglioneuromas and renal anomalies are induced by activated RET(MEN2B) in transgenic mice. 1002 63

The RET tyrosine kinase is a functional receptor for neurotrophic ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Loss of function of RET is associated with congenital megacolon or Hirschsprung's disease, whereas germ-line point mutations causing RET activation are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and familial medullary thyroid carcinoma) syndromes. Here we show that the expression of a constitutively active RET-MEN2A oncogene promotes survival of rat pheochromocytoma PC12 cells upon growth factor withdrawal. Moreover, we show that the RET-MEN2A-mediated survival depends on signals transduced by the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. Thus, in PC12 cells, RET-MEN2A associates with the PI3K regulatory subunit p85 and promotes activation of Akt (also referred to as protein kinase B) in a PI3K-dependent fashion; in addition, RET-MEN2A promotes MAPK activation. PI3K recruitment and Akt activation as well as MAPK activation depend on RET-MEN2A tyrosine residue 1062. As a result, tyrosine 1062 of RET-MEN2A is essential for RET-MEN2A-mediated survival of PC12 cells cultured in growth factor-depleted media.
 ...
PMID:Tyrosine 1062 of RET-MEN2A mediates activation of Akt (protein kinase B) and mitogen-activated protein kinase pathways leading to PC12 cell survival. 1091 41

Protein-tyrosine-phosphatases (PTPs), in conjunction with protein-tyrosine kinases, play essential regulatory roles in diverse cellular activities by modulating the phosphorylation state of target proteins. Leukocyte common antigen-related (LAR) protein is a widely expressed receptor-type protein-tyrosine-phosphatase that is implicated in the regulation of intracellular signaling triggered by both cell adhesion and peptide growth factors. The gene for LAR is localized to human chromosome 1p32, a region frequently deleted in tumors of neuroectodermal origin, including neuroblastoma, pheochromocytoma, and medullary thyroid carcinoma. On the other hand, the RET gene codes for a transmembrane tyrosine kinase and is responsible for the development of multiple endocrine neoplasia (MEN) 2A and 2B. To explore the potential role of LAR in RET tyrosine kinase activity and RET-induced signal transduction, we cotransfected LAR and RET with a MEN2A or MEN2B mutation (designated RET-MEN2A or RET-MEN2B) into the NIH 3T3 cell line. Here we show that LAR reduces the constitutive tyrosine autophosphorylation and kinase activity of RET-MEN2A but not RET-MEN2B, accompanying a significant decrease of phosphorylation of phospholipase Cgamma, AKT, and ERK1/2. Interestingly, LAR expression significantly decreased the levels of disulfide-linked RET-MEN2A dimerization. Moreover, reduced oncogenic activity of RET-MEN2A by overexpression of LAR was observed both by an in vitro colony formation assay and by in vivo tumorigenicity in scid mice. These results thus suggest that LAR may contribute to deactivation of the RET-MEN2A mutant protein and reduction of its oncogenic activity in vivo.
 ...
PMID:Differential effects of leukocyte common antigen-related protein on biochemical and biological activities of RET-MEN2A and RET-MEN2B mutant proteins. 1112 8

Mutations of the Ret receptor tyrosine kinase are responsible for inheritance of multiple endocrine neoplasia (MEN2A and MEN2B) and familial medullary thyroid carcinoma syndromes. Although several familial medullary thyroid carcinoma and most MEN2A mutations involve substitutions of extracellular cysteine residues, in most MEN2B cases there is a methionine-to-threonine substitution at position 918 (M918T) of the Ret kinase domain. The mechanism by which the MEN2B mutation converts Ret into a potent oncogene is poorly understood. Both MEN2A and MEN2B oncoproteins exert constitutive activation of the kinase. However, the highly aggressive MEN2B phenotype is not supported by higher levels of Ret-MEN2B kinase activity compared with Ret-MEN2A. It has been proposed that Ret-MEN2B is more than just an activated Ret kinase and that the M918T mutation, by targeting the kinase domain of Ret, might alter Ret substrate specificity, thus affecting Ret autophosphorylation sites and the ability of Ret to phosphorylate intracellular substrates. We show that the Ret-MEN2B mutation causes specific potentiated phosphorylation of tyrosine 1062 (Y1062) compared with Ret-MEN2A. Phosphorylated Y1062 is part of a Ret multiple effector docking site that mediates recruitment of the Shc adapter and of phosphatidylinositol-3 kinase (PI3K). Accordingly, we show that Ret-MEN2B is more active than Ret-MEN2A in associating with She and in causing constitutive activation of the Ras/mitogen-activated protein kinase and PI3K/Akt cascades. We conclude that the MEN2B mutation specifically potentiates the ability of Ret to autophosphorylate Y1062 and consequently to couple to the Ras/mitogen-activated protein kinase and the PI3K/Akt pathways. The more efficient triggering of these pathways may account for the difference between MEN2A and MEN2B syndromes.
 ...
PMID:Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. 1124 46

Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.
 ...
PMID:Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. 1138 85

Germline mutations in the Ret protooncogene give rise to the inherited endocrine cancer syndromes MEN types 2A and 2B and familiar medullary thyroid carcinoma. Although it is well accepted that the constitutive active tyrosine kinase of Ret oncogenes ultimately leads to malignant transformation, it is not clear whether a decrease in the autophosphorylation of oncogenic Ret forms can affect the mitogenic and transforming activities of Ret. Potential modulators of the tyrosine kinase activity of Ret could be tyrosine phosphatases that are expressed in human thyroid tissue. Therefore, we investigated the impact of the tyrosine phosphatases SHP1 and SHP2 on the intrinsic tyrosine kinase activity and oncogenic potency of Ret with a 9-bp duplication in the cysteine-rich domain (codons 634-636), which was described in a patient with MEN type 2A recently. SHP1 and SHP2 were stably overexpressed in NIH3T3 fibroblasts together with Ret-9bp. Coexpression of SHP1 with Ret-9bp reduced the autophosphorylation of Ret-9bp by 19 +/- 7% (P = 0.01, n = 4), whereas no effect was seen with SHP2. Furthermore, Ret-9bp could be coimmunoprecipitated with SHP1 but not with SHP2 antibodies. Suppression of the Ret-9bp tyrosine kinase activity by SHP1 caused a decrease in activation of Erk2 (extracellular signal-regulated kinase) and abolished PKB/Akt (protein kinase B) phosphorylation. In addition, diminished Ret-9bp autophosphorylation led to reduced phosphorylation of the transcription factor jun-D. Finally, the inhibitory effect on Ret-9bp signaling resulted in a 40-60% reduction of [(3)H]thymidine incorporation and in reduced ability of NIH3T3 cells to form colonies in soft agar. In conclusion, the data suggest that SHP1 caused a moderate reduction of Ret autophosphorylation, which led to a strong suppression of the Ret oncogene activity.
 ...
PMID:Inhibition of Ret oncogene activity by the protein tyrosine phosphatase SHP1. 1156 8


1 2 3 4 5 Next >>