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)

In murine fibroblasts activation of the Shc/Grb-2 pathway by the ErbB-2 kinase involves tyrosine phosphorylation of Shc products and the formation of Shc/ErbB-2, Shc/Grb-2 and Grb-2/ErbB-2 complexes. Tyr 1139 of ErbB-2 bound to the Grb-2 SH2 domain in vitro as well as in intact cells. Tyr 1221 and 1248 are binding sites of gp185ErbB-2 for Shc SH2 domain in vitro whereas Tyr 1196 and 1248 are major binding sites of ErbB-2 for Shc PTB domain. Inhibition of Shc/ErbB-2 complex formation in intact cells was obtained by simultaneous mutational inactivation of Shc SH2 and Shc PTB binding sites of gp185ErbB-2. Shc/ErbB-2 complexes are formed upon activation of the ErbB-2 kinase and tyrosine phosphorylation of Shc proteins; they are located in both cytosol and cellular membranes. ErbB-2 activation induces also translocation of Grb-2 from cytosol to membranes. This network of protein-protein interactions may reflect the ability of the Shc/Grb-2 pathway to act as a molecular switch controlling different cellular functions regulated by RTK activation. In fact the Ras GDP exchanger mSOS was recruited in Grb-2/ErbB-2 complexes; furthermore besides mSOS, other polypeptides present in either cytosolic or membrane preparations were able to complex in vitro with Grb-2 SH3 domains.
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PMID:Analysis of protein-protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. 747 76

Activating germline mutations of the RET receptor tyrosine kinase are found in the majority of cases of inherited cancer syndrome MEN 2, and inactivating mutations in some cases of dominantly inherited Hirschsprung disease. Using RET activated by a MEN 2 mutation, we show that both the SH2 and PTB domains of the adaptor protein Shc interact with RET, and we identify the PTB domain interaction site. Interaction with both the SH2 and PTB domains of Shc contributes to the transcriptional activation of a serum response element. RET alternate splicing affects the strength of interaction with both the Shc SH2 and PTB domains. In addition, a splice isoform-specific HSCR missense mutation, which does not inactivate the RET kinase activity, decreases the strength of the PTB domain interaction and the level of RET-dependent Shc phosphorylation.
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PMID:RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2. 904 83

The RET proto-oncogene encodes two isoforms of a receptor type tyrosine kinase which plays a role in neural crest and kidney development. Distinct germ-line mutations of RET have been associated with the inherited cancer syndromes MEN2A, MEN2B and FMTC as well as with the congenital disorder Hirschsprung disease (HSCR), whereas somatic rearrangements (RET/PTCs) have been frequently detected in the papillary thyroid carcinoma. Despite these findings, suggesting a relevant role for RET product in development and neoplastic processes, little is known about the signalling triggered by this receptor. In this study, we have demonstrated that the transducing adaptor molecule Shc is recruited and activated by both Ret isoforms and by the rearranged cytoplasmatic Ret/ptc2 oncoproteins as well as by the membrane bound receptor activated by MEN2A or by MEN2B associated mutations. Moreover, our analysis has identified the Ret tyrosine residue and the Shc domains involved in the interaction. In fact, here we show that both the phosphotyrosine binding domains of Shc, PTB and SH2, interact with Ret/ptc2 in vitro. However, PTB domain binds 20 folds higher amount of Ret/ptc2 than SH2. The putative binding site for either SH2 and PTB domains has been identified as Tyr586 of Ret/ptc2 (Tyr1062 on proto-Ret). In keeping with this finding, by using RET/PTC2-Y586F mutant, we have demonstrated that this tyrosine residue, the last amino acid but one before the divergence of the two Ret isoforms, is the docking site for Shc.
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PMID:Identification of Shc docking site on Ret tyrosine kinase. 904 84

RET proto-oncogene mutation results in a dominant autosomic inherited syndrome (MEN 2) presenting three distinct subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). Detection of RET proto-oncogene mutation is a predictor before clinical or biochemical evidence of the disease is present and leads to preventive thyroid removal since there is no effective treatment for metastases. The aim of the present study was to characterize mutations in the RET proto-oncogene in affected patients and to identify potential carriers in their families. Two families with FMTC (5 and 6 members), 4 with MEN 2A (5, 5, 4 and 3 members) and 2 with MEN 2B (5 and 1 members), were studied. DNA was obtained from blood samples in all patients and from thyroid or from pheonochromocytoma tissues in patients submitted to surgery. PCR amplification was performed using specific primers for exons 10, 11 and 16, followed by direct sequencing. Mutations at codon 634 in exon 11 were found in 16 subjects with FMTC and MEN 2A: TGC --> CGC (cysteine to arginine) in 9 cases, TGC --> TAC (cysteine to tyrosine) in 3, and TGC --> TTC (cysteine to phenilalanine) in 4. A unique mutation of codon 918 in exon 16, ATG --> ACG (methionine to threonine), was found in both MEN 2B affected patients. The mutations detected in DNA from peripheral blood were the same as those present in DNA extracted from tumor material. RET mutations were detected in all affected patients, confirming the diagnosis, and in 10 members of their families. In five of the carriers total thyroidectomy was performed. Anatomopathological study showed C-cells hyperplasia or in-situ microcarcinoma in two children (9 and 12 y) with no clinical signs of diseases and medullary thyroid carcinoma in three adults, who were previously unaware of the presence of thyroid nodules. The early detection of RET mutation followed by total thyroidectomy may prevent the development of the disease, specially in affected families, and avoid the fatal outcome of delayed medullary thyroid carcinoma diagnosis.
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PMID:[Early diagnosis of multiple endocrine neoplasia type 2 (MEN 2) by detection of mutated RET proto-oncogene carriers]. 970 52

We examined RET protooncogene mutations in sporadic medullary thyroid carcinoma (MTC), using polymerase chain reaction (PCR)-based sequencing. DNA was extracted from tumor tissue and peripheral blood leukocytes of seven unrelated individuals with apparently sporadic MTC. Oligonucleotide primers were selected to amplify exons 10, 11, 13, 15, and 16 of the RET protooncogene, to examine the sequences of codons 609, 611, 618, and 620 of exon 10, codon 634 of exon 11, codon 768 of exon 13, codon 883 of exon 15, and codon 918 of exon 16. Direct DNA sequencing from PCR products was then performed. The results showed that one patient had a somatic mutation at codon 918 (ATG-->ACG), causing a Met-->Thr substitution. One patient had a de novo germline mutation at codon 634 (TGC-->CGC), causing a Cys-->Arg substitution. Another patient had a germline mutation at codon 634 (TGC-->TTC), causing a Cys-->Phe substitution. In the remaining four cases, no RET mutations were found. Unexpectedly, two offspring of the patient (a female) with a germline mutation at codon 634 (TGC-->TTC) harbored homozygous alleles for the mutation; because the father did not carry this mutation, the other affected allele was suspected to have resulted from a de novo germline mutation of paternal origin. One of these offspring was subsequently diagnosed as having MTC. Our findings suggest that all patients with apparently sporadic MTC should be screened for the RET protooncogene by molecular analysis to detect occult or de novo multiple endocrine neoplasia 2 (MEN 2) or familial MTC. This would allow early treatment of affected family members.
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PMID:RET protooncogene mutations in patients with apparently sporadic medullary thyroid carcinoma. 974 64

Vascular endothelial growth factor (VEGF) is one of the major angiogenesis regulators. It binds to its tyrosine kinase receptors, KDR and Flt-1. However, little is known about their downstream signal transduction properties. We screened human brain cDNA library using the yeast two-hybrid system with the KDR cytoplasmic region as bait to find KDR binding proteins. After 6.2 x 10(6) clones were screened, we identified Sck, one of the Shc homologues, as a KDR binding protein. Sck also binds to Flt-1 and their binding is dependent on the kinase activities of KDR and Flt-1. Extensive site-directed mutagenesis of KDR revealed that Y1175 of KDR is a major binding site for Sck. As Sck contains the SH2 domain and PTB domain, we tested whether they bind to KDR and Flt-1. The SH2 domain of Sck binds to both of them. Deletion of the SH2 domain from Sck resulted in the complete loss of binding. On the other hand, the PTB domain of Sck does not bind to KDR and Flt-1. These results indicate that Sck binds to KDR and Flt-1 via its SH2 domain and might play an important role in VEGF signal transduction.
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PMID:Sck interacts with KDR and Flt-1 via its SH2 domain. 979 Sep 10

The VEGFR3/FLT4 receptor, which is involved in vasculogenesis and angiogenesis, binds and phosphorylates SHC proteins on tyrosine residues. SHC contains two phosphotyrosine interaction domains: a PTB (Phosphotyrosine Binding) and a SH2 (Src Homology 2) domain. Previous studies have shown that SHC proteins are phosphorylated on Y239/Y240 and Y313 (Y317 in humans) by tyrosine kinases such as the EGF and IL3 receptors. We have investigated which of the SHC tyrosine residues are targeted by the VEGFR3/ FLT4 kinase and the role of the SHC PTB and SH2 domains in this process. Our results show that Y239/ Y240 and Y313 are simultaneously phosphorylated by the kinase, creating GRB2 binding sites. Mutation of SHC PTB, but not SH2, domain interferes with the SHC phosphorylation by VEGFR3/FLT4. Soft agar assay experiments revealed that the VEGFR3/FLT4 transforming capacity is increased by the mutation of Y239/Y240 to phenylalanines in SHC, suggesting that these two residues mediate an inhibitory signal for cell growth. Mutation of the two phosphorylation sites increases this effect, suggesting that they have a synergistic role.
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PMID:Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling. 992 7

The discoidin domain receptor (DDR1) is characterized by a discoidin I motif in the extracellular domain, an unusually long cytoplasmic juxtamembrane (JM) region, and a kinase domain that is 45% identical to that of the NGF receptor, TrkA. DDR1 also has a major splice form, which has a 37 amino acid insert in the JM region with a consensus Shc PTB site that is lacking in the shorter receptor. One class of ligands for the DDR receptors has recently been identified as being derived from the collagen family, but neither native PC12 cells, which express modest amounts of DDR1, nor transfected PC12 cells, which express much larger amounts of DDR1, respond to this ligand. A chimeric receptor, containing the extracellular domain of hPDGFRbeta fused to the transmembrane and intracellular regions of DDR1, also fails to mediate neuronal-like differentiation in stably transfected PC12 cells and is only weakly autophosphorylated. However, chimeric receptors, which are composed of combinations of intracellular regions from DDR1 and TrkA (with the extracellular domain of hPDGFRbeta), in some cases provided ligand (PDGF) -inducible receptor responses. Those with the TrkA kinase domain and the DDR1 JM regions were able to produce differentiation to varying degrees, whereas the opposite combination did not. Analysis of the signaling responses of the two chimeras with DDR1 JM sequences (with and without the insert) indicated that the shorter sequence bound and activated FRS2 whereas the insert-containing form activated Shc instead. Both activated PLCgamma through the carboxyl-terminal tyrosine of the TrkA domain (Y785 in TrkA residue numbering). Mutation of this site (Y-->F) eliminated PLCgamma activation (indicating there are no other cryptic binding sites for PLCgamma in the DDR1 sequences) and markedly reduced the differentiative activity of the receptor. This is in contrast to TrkA (or PDGFRbeta/TrkA chimeras), where ablation of this pathway has no notable effect on PC12 cell morphogenic responses. Thus, the activation of FRS2 and Shc (leading to MAPK activation) is weaker in the DDR1/TrkA chimeras than in TrkA alone, and the PLCgamma contribution becomes essential for full response. Nonetheless, both DDR1 JM regions contain potentially usable signaling sites, albeit they apparently are not activated directly in DDR1 (or DDR1 chimeras) in a ligand-dependent fashion. These findings suggest that the DDR1 receptors do have signaling capacity but may require additional components or altered conditions to fully activate their kinase domains and/or sustain the activation of the JM sites.
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PMID:Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors. 1078 52

To explore the potential of using the recombinant adeno-associated viral (rAAV) vector, expressing glial cell line-derived neurotrophic factor (GDNF) as the gene therapy for stroke, we injected rAAV vectors expressing GDNF (rAAV-GDNF) into the cortex of rats which had been experiencing transient bilateral common carotid artery ligation and right middle cerebral artery ligation for 90 min. GDNF levels in cortical tissues of rAAV-GDNF-injected animals were significantly higher than in the control animals injected with rAAV-expressing lacZ (rAAV-lacZ), indicating that rAAV can deliver and express the GDNF gene in cortical tissues. Triphenyltetrazolium chloride tissue stain analysis revealed that the rAAV-delivered GDNF gene could rescue the brain tissues from ischemia-induced injury. Cortical tissues which received rAAV-GDNF injections had both significantly smaller total volumes of infarction and smaller areas of infarction on each brain slice than those which were injected with rAAV-lacZ. An in situ labeling analysis demonstrated significantly less apoptotic cells in cortical tissues rescued by rAAV-GDNF, indicating prevention of apoptosis as the mechanism of cortical cell protection. Moreover, immunohistochemistry staining of Neu-N indicated that the rescued brain tissues contained the same number of Neu-N-positive neuronal cells as contralateral undamaged brain tissues. This provides strong evidence that cortical neuronal cells can be rescued by GDNF gene therapy. Indeed, these findings show that the rAAV is a potential delivery vector of GDNF gene for the therapy of stroke.
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PMID:Recombinant adeno-associated virus vector expressing glial cell line-derived neurotrophic factor reduces ischemia-induced damage. 1108 92

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.
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PMID:A large family with hereditary MTC: role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC. 1128 Jul 16


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