Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The A(2A)-adenosine receptor, a prototypical G(s)-coupled receptor, activates mitogen-activated protein (MAP) kinase in a manner independent of cAMP in primary human endothelial cells. In order to delineate signaling pathways that link the receptor to the regulation of MAP kinase, the human A(2A) receptor was heterologously expressed in Chinese hamster ovary (CHO) and HEK293 cells. In both cell lines, A(2A) agonist-mediated cAMP accumulation was accompanied by activation of the small G protein rap1. However, rap1 mediates A(2A) receptor-dependent activation of MAP kinase only in CHO cells, the signaling cascade being composed of G(s), adenylyl cyclase, rap1, and the p68 isoform of B-raf. This isoform was absent in HEK293 cells. Contrary to CHO cells, in HEK293 cells activation of MAP kinase by A(2A) agonists was not mimicked by 8-bromo-cAMP, was independent of Galpha(s), and was associated with activation of p21(ras). Accordingly, overexpression of the inactive S17N mutant of p21(ras) and of a dominant negative version of mSos (the exchange factor of p21(ras)) blocked MAP kinase stimulation by the A(2A) receptor in HEK 293 but not in CHO cells. In spite of the close homology between p21(ras) and rap1, the S17N mutant of rap1 was not dominant negative because (i) overexpression of rap1(S17N) failed to inhibit A(2A) receptor-dependent MAP kinase activation, (ii) rap1(S17N) was recovered in the active form with a GST fusion protein comprising the rap1-binding domain of ralGDS after A(2A) receptor activation, and (iii) A(2A) agonists promoted the association of rap1(S17N) with the 68-kDa isoform of B-raf in CHO cells. We conclude that the A(2A) receptor has the capacity two activate MAP kinase via at least two signaling pathways, which depend on two distinct small G proteins, namely p21(ras) and rap1. Our observations also show that the S17N version of rap1 cannot be assumed a priori to act as a dominant negative interfering mutant.
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PMID:Activation of mitogen-activated protein kinase by the A(2A)-adenosine receptor via a rap1-dependent and via a p21(ras)-dependent pathway. 1046 24

The ERK group of mitogen-activated protein kinases (MAPKs) is essential for cell proliferation stimulated by mitogens, oncogenic ras and raf (ref. 1). All MAPKs are activated by MAP3K/MEK/MAPK core pathways and the Raf proto-oncoproteins, especially B-Raf, are ERK-specific MAP3Ks (refs 1-3). Mixed lineage kinase-3 (MLK3) is a MAP3K that was thought to be a cytokine-activated, and comparatively selective, regulator of the JNK group of MAPKs (refs 1, 4-6). Here we report that silencing of mlk3 by RNAi suppressed mitogen and cytokine activation not only of JNK but of ERK and p38 as well. Silencing mlk3 also blocked mitogen-stimulated phosphorylation of B-Raf at Thr 598 and Ser 601, a step required for B-Raf activation. Furthermore, silencing mlk3 prevented serum-stimulated cell proliferation and the proliferation of tumour cells bearing either oncogenic Ki-Ras or loss-of-function neurofibromatosis-1 (NF1) or NF2 mutations. The proliferation of tumour cells containing activating B-raf or raf-1 mutations was unaffected by silencing mlk3. Our results define an unexpected role for MLK3 in mitogen regulation of B-Raf, ERK and cell proliferation.
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PMID:MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. 1530 91

Raf kinases play an integral role in the classic mitogen-activated protein (MAP) kinase (Raf/MEK/extracellular signal-related kinase [ERK]) intracellular signaling cascade, but their role in specific developmental processes is largely unknown. Using a genetic approach, we have identified a role for B-Raf during hematopoietic progenitor cell development and during megakaryocytopoiesis. Fetal liver and in vitro embryonic stem (ES) cell-derived myeloid progenitor development is quantitatively impaired in the absence of B-Raf. Biochemical data suggest that this phenotype is due to the loss of a normally occurring rise in B-Raf expression and associated ERK1/2 activation during hematopoietic progenitor cell formation. However, the presence of B-raf-/- ES cell-derived myeloid progenitors in the bone marrow of adult chimeric mice indicates the lack of an obligate cell-autonomous requirement for B-Raf in myeloid progenitor development. The lack of B-Raf also impairs megakaryocytopoiesis. Thrombopoietin (Tpo)-induced in vitro expansion of ES cell-derived megakaryocyte-lineage cells fails to occur in the absence of B-Raf. Moreover, this quantitative in vitro defect in megakaryocyte-lineage expansion is mirrored by chimeric mice data that show reduced B-raf-/- genotype contribution in megakaryocytes relative to its contribution in myeloid progenitors. Together, these data suggest that B-Raf plays a cell-autonomous role in megakaryocytopoiesis and a permissive role in myeloid progenitor development.
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PMID:A critical function for B-Raf at multiple stages of myelopoiesis. 1578 29

Mutations in the B-raf gene have been reported in a number of human cancers, including melanoma and lung cancer. More than 80% of the reported B-raf mutations were V599E; however, non-V599E mutations have been frequently found in non-small cell lung cancers as compared with melanoma. Some non-V599E mutations have been found surrounding Thr439, which is thought likely to be one of the three Akt phosphorylation sites in the B-raf protein. However, as a previous report indicated that Thr439 was not phosphorylated by Akt, the functional consequences of these mutations have been unclear. Here, we examined the effects of cancer-related B-raf mutations surrounding Thr439 on the activation of the mitogen-activated protein/ extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (Erk) pathway and the transformation of NIH 3T3 fibroblasts. Among the three reported mutations (K438Q, K438T, and T439P) found in non-small cell lung carcinoma and melanoma, none elevated the activity of the MEK/Erk cascade as determined by in vitro kinase assays, immunoblots using antibody specific for phosphorylated Erk, or Elk1-dependent reporter assays. The inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling by LY294002 increased the Erk activation induced by the mutant B-raf proteins, as well as by wild-type B-raf. Furthermore, the B-raf mutants did not have increased NIH 3T3-transforming activities, as determined by colony-formation assays. These results suggest that the B-raf mutations surrounding Thr439 found in human cancers are unlikely to contribute to increased oncogenic properties of B-raf.
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PMID:Functional consequences of mutations in a putative Akt phosphorylation motif of B-raf in human cancers. 1579 48

The mitogen-activated protein kinase (MAPK; i.e., Ras-Raf-Erk) pathway is an attractive target for therapeutic intervention in melanoma due to its integral role in the regulation of proliferation, invasiveness, and survival and the recent availability of pharmaceutical agents that inhibit the various kinases and GTPases that comprise the pathway. Genetic studies have identified activating mutations in either B-raf or N-ras in most cutaneous melanomas. Other studies have delineated the contribution of autocrine growth factors (e.g., hepatocyte growth factor and fibroblast growth factor) to MAPK activation in melanoma. Still, others have emphasized the consequences of the down-modulation of endogenous raf inhibitors, such as Sprouty family members (e.g., SPRY2) and raf-1 kinase inhibitory protein, in the regulation of the pathway. The diversity of molecular mechanisms used by melanoma cells to ensure the activity of the MAPK pathway attests to its importance in the evolution of the disease and the likelihood that inhibitors of the pathway may prove to be highly effective in melanoma treatment. MAPK inhibition has been shown to result in the dephosphorylation of the proapoptotic Bcl-2 family members Bad and Bim. This process in turn leads to caspase activation and, ultimately, the demise of melanoma cells through the induction of apoptosis. Several recent studies have identified non-mitogen-activated protein/extracellular signal-regulated kinase kinase-binding partners of raf and suggested that the prosurvival effects of raf and the lethality of raf inhibition are mediated through these alternative targets, independent of the MAPK pathway. Other studies have suggested that endothelial cells are the primary targets of raf inhibitors in vivo and that the antitumor effect of these agents are largely attributable to angiogenesis inhibition. This article reviews the genetic and biochemical factors contributing to MAPK activation in melanoma, the mechanisms by which inhibition of the pathway might prove deleterious to tumor cells, and the potential of MAPK inhibitors in the treatment of the disease.
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PMID:Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. 1660 61

Gene mutations can induce cellular alteration and malignant transformation. Development of many types of cancer is associated with mutations in the B-raf proto-oncogene (BRAF) gene. The encoded protein is a component of the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway, transmitting information from the outside to the cell nucleus. The main function of the MAPK/ERK pathway is to regulate cell growth, migration, and proliferation. The most common mutations in the BRAF gene encode the V600E mutant (class I), which causes continuous activation and signal transduction, regardless of external stimulus. Consequently, cell proliferation and invasion are enhanced in cancer patients with such mutations. The V600E mutation has been linked to melanoma, colorectal cancer, multiple myeloma, and other types of cancers. Importantly, emerging evidence has recently indicated that new types of mutations (classes II and III) also play a paramount role in the development of cancer. In this minireview, we discuss the influence of various BRAF mutations in cancer, including aberrant transcriptional gene regulation in the affected tissues.
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PMID:Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks. 3319 72