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)

SNT/FRS2 is a lipid anchored docking protein that contains an amino-terminal myristylation signal, followed by a phosphotyrosine-binding (PTB) domain and a carboxy-terminal region with multiple tyrosine residues. Here we show that the SNT/FRS2 PTB domain binds to RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF) or multiple endocrine neoplasia (MEN) 2 mutations. Analyses by site directed-mutagenesis revealed that it binds to tyrosine 1062 in RET that is also known to be a binding site for the SHC adaptor protein. Whereas SHC bound to RET was associated with GRB2 and GAB1 proteins, SNT/FRS2 was associated with GRB2 only, suggesting that SNT/FRS2 is involved mainly in the activation of the RAS/mitogen activated protein kinase (MAPK) pathway but not the phosphatidylinositol 3-kinase (PI3-K)/AKT pathway. In addition, phosphorylated SNT/FRS2 appeared to directly complex with SHP-2 tyrosine phosphatase. These results suggest that tyrosine 1062 in RET provides a site for the interaction of multiple signaling molecules and that the balance of SHC and SNT/FRS2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated RET.
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PMID:Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. 1136 Jan 77

The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for "glial cell-derived neurotrophic factors") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation of FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation. These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas.
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PMID:Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. 1139 Jun 47

Several genetic studies in Drosophila have shown that the dSprouty (dSpry) protein inhibits the Ras/mitogen-activated protein (MAP) kinase pathway induced by various activated receptor tyrosine kinase receptors, most notably those of the epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR). Currently, the mode of action of dSpry is unknown, and the point of inhibition remains controversial. There are at least four mammalian Spry isoforms that have been shown to co-express preferentially with FGFRs as compared with EGFRs. In this study, we investigated the effects of the various mammalian Spry isoforms on the Ras/MAP kinase pathway in cells overexpressing constitutively active FGFR1. hSpry2 was significantly more potent than mSpry1 or mSpry4 in inhibiting the Ras/MAP kinase pathway. Additional experiments indicated that full-length hSpry2 was required for its full potency. hSpry2 had no inhibitory effect on either the JNK or the p38 pathway and displayed no inhibition of FRS2 phosphorylation, Akt activation, and Ras activation. Constitutively active mutants of Ras, Raf, and Mek were employed to locate the prospective point of inhibition of hSpry2 downstream of activated Ras. Results from this study indicated that hSpry2 exerted its inhibitory effect at the level of Raf, which was verified in a Raf activation assay in an FGF signaling context.
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PMID:Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf. 1169 4

Fibroblast growth factor receptors (FGFRs) are a family of transmembrane tyrosine kinases involved in signaling via interactions with the family of fibroblast growth factors. Alternative splicing of the juxtamembrane region of FGFR1-3 leads to the inclusion or exclusion of two amino acids, valine and threonine, the VT site. The presence or absence of VT (VT+ or VT-, respectively) affects the signaling potential of the receptor. The VT+ receptor isoform is required for Erk2 phosphorylation, a component of the mitogen-activated protein kinase signaling pathway. FRS2 is an adaptor protein that links FGFRs to the mitogen-activated protein kinase signaling pathway. FRS2 interacts with a region of the juxtamembrane domain of FGFR1 that includes the alternatively spliced VT site. We investigated the interaction of FRS2 with murine Fgfr1 juxtamembrane domain. We showed the alternatively spliced VT motif, at the juxtamembrane domain of Fgfr1 is required for FRS2 interaction with Fgfr1. Activation of signaling pathways from FRS2 is likely to be regulated by controlling the Fgfr1/FRS2 interaction through alternative splicing of the VT motif of Fgfr1.
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PMID:Association of the signaling adaptor FRS2 with fibroblast growth factor receptor 1 (Fgfr1) is mediated by alternative splicing of the juxtamembrane domain. 1172 84

Membrane-anchored adaptor proteins FRS2alpha/beta (also known as SNT-1/2) mediate signaling of fibroblast growth factor receptors (FGFRs) and neurotrophin receptors (TRKs) through their N-terminal phosphotyrosine binding (PTB) domains. The FRS2 PTB domain recognizes tyrosine-phosphorylated TRKs at an NPXpY (where pY is phosphotyrosine) motif, whereas its constitutive association with FGFR involves a receptor juxtamembrane region lacking Tyr and Asn residues. Here we show by isothermal titration calorimetry that the FRS2alpha PTB domain binding to peptides derived from TRKs or FGFR is thermodynamically different. TRK binding is largely enthalpy-driven, whereas the FGFR interaction is governed by a favorable entropic contribution to the free energy of binding. Furthermore, our NMR spectral analysis suggests that disruption of an unstructured region C-terminal to the PTB domain alters local conformation and dynamics of the residues at the ligand-binding site, and that structural disruption of the beta8-strand directly weakens the PTB domain association with the FGFR ligand. Together, our new findings support a molecular mechanism by which conformational dynamics of the FRS2alpha PTB domain dictates its association with either fibroblast growth factor or neurotrophin receptors in neuronal development.
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PMID:FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. 1187 85

Ligand activation of the fibroblast growth factor receptor (FGFR) represses myogenesis and promotes activation of extracellular signal-regulated kinases 1 and 2 (Erks). The precise mechanism through which the FGFR transmits both of these signals in myoblasts remains unclear. The SH2 domain-containing protein tyrosine phosphatase, SHP-2, has been shown to participate in the regulation of FGFR signaling. However, no role for SHP-2 in FGFR myogenic signaling is known. In this study, we show that stimulation of C2C12 myoblasts with FGF-2 induces SHP-2 complex formation with tyrosyl-phosphorylated FGFR substrate 2 alpha (FRS-2 alpha). Both the catalytic activity and, to a much lesser extent, the Grb2 binding-tyrosyl phosphorylation sites of SHP-2 are required for maximal FGF-2-induced Erk activity and Elk-1 transactivation. When overexpressed in C2C12 myoblasts, wild-type SHP-2, but not a catalytically inactive SHP-2 mutant, potentiates the suppressive effects of FGF-2 on muscle-specific gene expression. In addition, expression of a constitutively active mutant of SHP-2 is sufficient to prevent myogenesis. The constitutively active mutant of SHP-2 induces hyper-tyrosyl phosphorylation of FRS-2 alpha but fails to stimulate or potentiate either FGF-2-induced Erk activation or Elk-1 transactivation. These data suggest that in myoblasts, SHP-2 represses myogenesis via a pathway that is independent of the Erks. We propose that SHP-2 plays a pivotal role in FGFR signaling in myoblasts via both Erk-dependent and Erk-independent pathways.
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PMID:Role of SHP-2 in fibroblast growth factor receptor-mediated suppression of myogenesis in C2C12 myoblasts. 1199 21

A partnership between the ectodomain of the fibroblast growth factor receptor (FGFR) isotypes and the chains of pericellular matrix heparan sulfate determines the fibroblast growth factor (FGF) and cell-type specificitives of the FGFR signaling complex. The contribution of the FGFR intracellular tyrosine kinase domains to the specificity of FGFR signaling is unclear. This report shows that the quantity and quality of phosphorylation of the FGFR kinase substrate SNT1 (also called FGFR substrate 2, FRS2) is both FGFR isotype and cell-type specific in prostate tumor epithelial cells at different stages of malignancy. Epithelial cell-resident FGFR2 that promotes homeostasis yields a low level of phosphorylated 65-kDa SNT1. Phosphorylation by ectopic FGFR1 that promotes malignancy was much more intense and yielded a phosphorylated 85-kDa SNT1. The amount of the 85-kDa SNT1 increased by 20-fold during proliferative aging of FGFR1-expressing cell populations that is required for FGFR1-stimulated mitogenesis and the malignant phenotype. In addition, the receptor-specific differential phosphorylation of SNT1 by FGFR isotypes, both of which are normally anchored to the cell membrane, occurred only in intact cells. Therefore, similar to kinase subunits within the heparan sulfate-FGFR complex, cell membrane and cytoskeletal context likely determine FGFR isotype- and cell-type-specific conformational relationships between FGFR kinases and external substrates. This determines the quantity and quality of SNT1 phosphorylation and differential signaling.
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PMID:Cell- and receptor isotype-specific phosphorylation of SNT1 by fibroblast growth factor receptor tyrosine kinases. 1202 67

Mutations that produce oncogenes with dominant gain of function target receptor protein tyrosine kinases (PTKs) in cancer and confer uncontrolled proliferation, impaired differentiation, or unrestrained survival to the cancer cell. However, insufficient PTK signaling may be responsible for developmental diseases. Gain of function of the RET receptor PTK is associated with human cancer. At the germline level, point mutations of RET are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and FMTC). Mutations of extracellular cysteines are found in MEN2A patients, and a Met918Thr mutation is responsible for most MEN2B cases. At the somatic level, gene rearrangements juxtaposing the tyrosine kinase domain of RET to heterologous gene partners are found in papillary carcinomas of the thyroid. These rearrangements generate the chimeric RET/PTC oncogenes. Both MEN2 mutations and PTC gene rearrangements potentiate the intrinsic tyrosine kinase activity of RET and, ultimately, the RET downstream signaling events. A multidocking site of the C-tail of RET is essential for both mitogenic and survival RET signaling. Such a site is involved in the recruitment of several intracellular molecules, such as the Shc, FRS2, IRS1, Gab1/2, and Enigma. The different activating mutations not only potentiate the enzymatic activity of the RET kinase but also may alter qualitatively RET signaling properties by: (1) altering RET autophosphorylation (in the case of the MEN2B mutation), (2) modifying the subcellular distribution of the active kinase, and (3) providing the active kinase with a scaffold for novel protein-protein interactions (as in the case of RET/PTC oncoproteins). This review describes the molecular mechanisms by which the different genetic alterations cause the conversion of RET into a dominant transforming oncogene.
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PMID:Molecular mechanisms of RET activation in human cancer. 1209 36

The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity.
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PMID:Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc. 2722 98

The thyroid TRK oncogenes are generated by chromosomal rearrangements juxtaposing the neurotrophic tyrosine receptor kinase type 1 (NTRK1) tyrosine kinase domain to foreign activating sequences. TRK oncoproteins display a constitutive tyrosine kinase activity resulting in the capability to transform NIH3T3 cells. The TRK oncoproteins' signal transduction has been in part elucidated, and it involves several signal transducers activated by the NGF-stimulated NTRK1 receptor. In this paper, we investigate the role of FRS2 and FRS3, two related adapter proteins activated by fibroblast growth factor and NTRK1 receptors, in the signaling of the thyroid TRK-T1 and TRK-T3 oncogenes. By a combination of in vitro and in vivo assays, we demonstrate that both fibroblast growth factor receptor substrate (FRS)2 and FRS3 are recruited and activated by TRK-T1 and TRK-T3. Interaction studies using different TRK-T3 mutants indicate that FRS3 is recruited by the same tyrosine residue interacting with Shc and FRS2. Expression studies show different expression patterns of the FRS adapters in normal and tumor thyroid samples: FRS3 is expressed in both normal and thyroid tumor samples, whereas FRS2 is not expressed in normal thyroid but is differentially expressed in some tumors. Altogether, our data indicate that the FRS2 and FRS3 adapters may have a role in thyroid carcinogenesis triggered by TRK oncogenes.
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PMID:The signaling adapters fibroblast growth factor receptor substrate 2 and 3 are activated by the thyroid TRK oncoproteins. 1258 69


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