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

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

Vascular endothelial growth factor (VEGF165) and its receptor KDR (kinase insert domain-containing receptor) are central regulators of blood vessel formation. We herein report a KDR-binding protein we have isolated in the venom of eastern cottonmouth (Agkistrodon piscivorus piscivorus). Sequence analysis revealed the isolated KDR-binding protein (designated KDR-bp) is identical to Lys49-phosholipase A2 (Lys49PLA2), an inactive PLA2 homologue with strong myotoxicity, in which Lys49 substitutes Asp49, a key residue for binding the essential cofactor Ca2+. KDR-bp binds to the extracellular domain of KDR with subnanomolar affinity. KDR-bp also binds to a lesser extent with Flt-1 and IgG but not to other receptors with similar immunoglobulin-like domain structures such as platelet-derived growth factor receptor alpha. The interaction between KDR-bp and KDR was blocked by VEGF165, and KDR-bp specifically inhibited VEGF165-stimulated endothelial cell proliferation, indicating KDR-bp is an antagonistic ligand for KDR. Lys49PLA2s from another snake venom were found to exhibit similar receptor binding properties to KDR-bp. This is the first report to demonstrate that an exogenous factor antagonizes VEGF and its receptor system. Our observation offers further insight into the as yet unknown molecular mechanism of myotoxic activity of snake venom Lys49PLA2s. Furthermore, KDR-bp would make a valuable tool for studying the structure and function of KDR, such as that expressed on skeletal muscle cells.
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PMID:Identification of vascular endothelial growth factor receptor-binding protein in the venom of eastern cottonmouth. A new role of snake venom myotoxic Lys49-phospholipase A2. 1601 30

The c-KIT and the platelet-derived growth factor receptor alpha (PDGFRalpha) have been shown to be important for tumor growth and progression in several soft-tissue sarcomas, including synovial sarcomas (SSs). It has been suggested that these c-KIT-positive cases might benefit from a tyrosine kinase inhibitor therapy. In this study, we analyze a series of SSs to investigate the presence of c-KIT and PDGFRalpha mutations with the aim of selecting those for a more adequate and appropriate therapy. We analyzed fresh-frozen tissues from 12 SSs (8 primary tumors and 4 nude mice xenotransplants from primary tumors). RNA was extracted to identify the presence of the SYT-SSX gene fusion to confirm the SS diagnosis. Mutational analysis of exons 9, 11, 13, and 17 of c-KIT and exons 12 and 18 of PDGFRalpha was performed by direct sequencing. Immunohistochemical analysis of c-KIT, PDGFRalpha, and p-PDGFRalpha was also performed. All analyzed cases showed the presence of SYT-SSX gene fusion transcripts confirming the diagnosis of SS, 10 carried the SYT-SSX1 fusion, and 2 the SYT-SSX2. Immunohistochemical analysis showed expression of c-KIT in 3 cases in which no molecular alterations were detected. For the PDGFRalpha, we observed an in-frame deletion of codons 554 and 555 in a case which also showed a strong immunopositivity for the phosphorylated form of PDGFRalpha. PDGFRalpha expression was observed in 8 cases. We suggest that a more exhaustive mutational analysis of the c-KIT and PDGFRalpha genes should be performed to ascertain which cases would really benefit from a tyrosine kinase inhibitor therapy in SS.
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PMID:Mutational analysis of the c-KIT AND PDGFRalpha in a series of molecularly well-characterized synovial sarcomas. 1610 93

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations of KIT or the platelet-derived growth factor receptor alpha gene (PDGFRA) have been identified in the vast majority of GISTs. The respective oncoproteins exhibit constitutive tyrosine kinase activity and promote cell growth. KIT and PDGFRA mutations are rarely found in GISTs in patients with neurofibromatosis type 1 (NF1) suggesting that the pathogenesis of GIST in NF1 patients is different from that in non-NF1 patients. Endoscopic diagnosis of GIST is usually difficult. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNAB) is a useful method for the diagnosis of GIST and for the detection of KIT or PDGFRA mutations. Imatinib mesylate, a tyrosine kinase inhibitor known to inhibit the activities of BCR-ABL, KIT, and PDGFR, is currently being used for the treatment of both chronic myeloid leukemia and metastatic GIST. The clinical response to imatinib therapy correlates with the types of mutations of KIT and PDGFRA, and the determination of KIT and PDGFRA mutations is useful for predicting the effect of imatinib. Resistance to imatinib after an initial response has been reported; secondary point mutations in KIT or PDGFRA that confer imatinib resistance are the most common mechanisms responsible for acquired resistance to imatinib. The continued development of target-specific therapies should increase the probability of cure in most patients with GISTs.
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PMID:Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors. 1614 81

Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor alpha) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C>A or C>G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A>T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, <or=5 mitoses/50 high power field was detected in six GISTs including larger, >5 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease.
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PMID:GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. 1625 21

Endothelial cells (ECs) are thought to be derived mainly from the vascular endothelial growth factor receptor 2 (VEGFR-2)+ lateral mesoderm during early embryogenesis. In this study, we specified several pathways for EC differentiation using a murine embryonic stem (ES) cell differentiation culture system that is a model for cellular processes during early embryogenesis. Based on the results of in vitro fate analysis, we show that, in the main pathway, committed ECs are differentiated through the VEGFR-2+ platelet-derived growth factor receptor alpha (PDGFR-alpha)- single-positive (VSP) population that is derived from the VEGFR-2+ PDGFR-alpha+ double-positive (DP) population. This major differentiation course was also confirmed using DNA microarray analysis. In addition to this main pathway, however, ECs also can be generated from the VEGFR-2- PDGFR-alpha+ single-positive (PSP) population, which represents the paraxial mesodermal lineage and is also derived from the DP population. Our results strongly suggest that, even after differentiation from the common progenitor DP population into the VSP and PSP populations, these two populations continue spontaneous switching of their surface phenotype, which results in switching of their eventual fates. The rate of this interlineage conversion between VSP and PSP is unexpectedly high. Because of this potential to undergo fate switch, we conclude that ECs can be generated via multiple pathways in in vitro ES cell differentiation.
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PMID:In vitro modeling of paraxial and lateral mesoderm differentiation reveals early reversibility. 1633 96

Eosinophilia sometimes occurs in acute myeloid leukemia (AML), especially in core binding factor (CBF) leukemia. However, the pathogenesis of the differentiation from leukemic progenitors to eosinophils is not well understood in this type of leukemia. Recent reports showed that a novel fusion tyrosine kinase, Fip1-like1 (FIP1L1) platelet-derived growth factor receptor alpha (PDGFRalpha), is found in idiopathic hypereosinophilic syndrome. The involvement of another chimeric gene, PDGFRbeta, was also reported in myeloproliferative disorder with eosinophilia. These chimeric genes cause constitutive activation of PDGFR tyrosine kinases. On the other hand, a two-hit model for the pathogenesis of AML, which seems to be caused by inactivating mutations in transcription factors and genetic lesions in tyrosine kinase resulting in constitutive activation, has been proposed. On the basis of these findings, we screened for the expression of the FIP1L1-PDGFRalpha fusion gene and for mutations in the juxtamembrane and tyrosine kinase domains of PDGFRalpha/beta genes in 22 cases of CBF leukemia with eosinophilia. Among these cases, no FIP1L1-PDGFRalpha fusion gene was found. Although cDNA sequencing also detected three types of single-nucleotide alterations at kinase domains in PDGFRalpha/beta genes, all of them were silent changes and polymorphisms. Therefore, PDGFRalpha/beta genes do not appear to play a significant pathogenetic role in eosinophilia or leukemogenesis of CBF leukemia.
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PMID:Molecular analysis of PDGFRalpha/beta genes in core binding factor leukemia with eosinophilia. 1634 67

The GTPase-deficient, activated mutant of Galpha12 (Galpha12Q229L, or Galpha12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor alpha (PDGFRalpha) in Galpha12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that Galpha12QL stimulates the functional expression of PDGFRalpha and demonstrate that the expression of PDGFRalpha by Galpha12QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of Galpha12QL or the activation of Galpha12-coupled receptors stimulates the expression of PDGFRalpha in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFRalpha in Galpha12QL-transformed cells. Analysis of the functional consequences of the Galpha12-PDGFRalpha signaling axis indicates that Galpha12 stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that Galpha12QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFRalpha- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFRalpha-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by Galpha12QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFRalpha attenuated Galpha12-mediated neoplastic transformation of NIH 3T3 cells.
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PMID:Transactivation of platelet-derived growth factor receptor alpha by the GTPase-deficient activated mutant of Galpha12. 1635 79

Leydig cells (LCs) are thought to differentiate from spindle-shaped precursor cells that exhibit some aspects of differentiated function, including 3beta-hydroxysteroid dehydrogenase (3betaHSD) activity. The precursor cells ultimately derive from undifferentiated stem LCs (SLCs), which are postulated to be present in testes before the onset of precursor cell differentiation. We searched for cells in the neonatal rat testis with the abilities to: (i) proliferate and expand indefinitely in vitro (self renew); (ii) differentiate (i.e., 3betaHSD and ultimately synthesize testosterone); and (iii) when transplanted into host rat testes, colonize the interstitium and subsequently differentiate in vivo. At 1 week postpartum, spindle-shaped cells were seen in the testicular interstitium that differed from the precursor cells in that they were 3betaHSD-negative, luteinizing hormone (LH) receptor (LHR)-negative, and platelet-derived growth factor receptor alpha (PDGFR alpha)-positive. These cells were purified from the testes of 1-week-old rats. The cells contained proteins known to be involved in LC development, including GATA4, c-kit receptor, and leukemia inhibitory factor receptor. The putative SLCs expanded over the course of 6 months while remaining undifferentiated. When treated in media that contained thyroid hormone, insulin-like growth factor I, and LH, 40% of the putative SLCs came to express 3betaHSD and to synthesize testosterone. When transplanted into host rat testes from which LCs had been eliminated, the putative SLCs colonized the interstitium and subsequently expressed 3betaHSD, demonstrating their ability to differentiate in vivo. We conclude that these cells are likely to be the sought-after SLCs.
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PMID:In search of rat stem Leydig cells: identification, isolation, and lineage-specific development. 1646 41

Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Both PDGFRalpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
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PMID:Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. 1706

The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA-positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRalpha) (T674I) mutant. Sorafenib inhibited the proliferation of FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha(T674I)-transformed Ba/F3 cells and induced apoptosis of the EOL-1 cell line at a low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha(T674I). Sorafenib was recently approved for the treatment of renal cell carcinoma. Our data suggest that low doses of sorafenib could be efficient for the treatment of FIP1L1-PDGFRA-positive CEL and could be used to overcome resistance to imatinib associated with the T674I mutation.
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PMID:Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant. 1664 67


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