| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.60596945 |
| Acute expression of RET / PTC ( Y541F ) appropriately interacted with Shc , an intermediate in the activation of the Ras pathway , but failed to activate PLCgamma . 0.60596945^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :1.0778623 |
| In treated cells , Ret / Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase C ( gamma ) , thereby indicating abrogation of constitutive signaling mediated by the oncoprotein . 1.0778623^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Mutation of Tyr 1062 ( Y1062F ) in the cytoplasmic tail of c Ret abolished receptor binding and phosphorylation of the adaptor Shc and eliminated activation of Ras by GDNF . ^^^ Ligand stimulation of neuronal cells induced the assembly of a large protein complex containing c Ret , Grb 2 , and tyrosine phosphorylated forms of Shc , p 85 ( PI3K ) , the adaptor Gab 2 , and the protein tyrosine phosphatase SHP 2 . ^^^ These results indicate that upon ligand stimulation , at least two distinct protein complexes assemble on phosphorylated Tyr 1062 of c Ret via Shc , one leading to activation of the Ras / Erk pathway through recruitment of Grb2 / Sos and another to the PI3K / Akt pathway through recruitment of Grb2 / Gab2 followed by p 85 ( PI3K ) and SHP 2 . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| A mutation at tyrosine 1062 in MEN2A Ret and MEN2B Ret impairs their transforming activity and association with shc adaptor proteins . ^^^ The Shc adaptor proteins bound to the MEN2A Ret and MEN2B Ret proteins and were phosphorylated on tyrosine in the transfectants . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| 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 . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| In vitro binding assay revealed that the long isoform of the MEN2A Ret protein and both isoforms of the MEN2B Ret protein bound preferentially to the Shc PTB domain . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Substitution of Ser for Ile 1057 ( I1057S ) , Ala for Asn 1059 ( N1059A ) , or Pro for Leu 1061 ( L1061P ) in this sequence significantly decreased the transforming activity of Ret with the multiple endocrine neoplasm type 2A ( MEN2A ) mutation as well as the binding affinity of Shc to it in vivo and in vitro , indicating that these three amino acids play a role in Shc binding . ^^^ As a result , we found that the transforming activity of Ret 43 isoform with the MEN2A mutation and the binding affinity of Shc to it were very low , although the consensus sequence for the binding of the Shc PTB domain is conserved in the Ret 43 isoform . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Previous studies have demonstrated that mutation of Tyr 1062 , which is the intracellular docking site for Shc and Enigma on RET , abolishes the RET MEN2A transforming activity . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Here , we show that triggering of GDNF affected only ret / MEN2B , i . e . it stimulated ret / MEN2B mitogenic and kinase activities , as well as its ability to phosphorylate Shc , a bona fide Ret substrate . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb 2 adaptor proteins . ^^^ We have shown that the SH 2 domain of the adaptor protein Shc coimmunoprecipitates with all the Ret and Trk oncoproteins as well as with NGF activated proto Trk receptor . ^^^ In addition , in cells containing either Ret or Trk oncoproteins , Shc proteins are constitutively phosphorylated on tyrosine and bound to Grb 2 . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| RET alternate splicing influences the interaction of activated RET with the SH 2 and PTB domains of Shc , and the SH 2 domain of Grb 2 . ^^^ Using RET activated by a MEN 2 mutation , we show that both the SH 2 and PTB domains of the adaptor protein Shc interact with RET , and we identify the PTB domain interaction site . ^^^ RET alternate splicing affects the strength of interaction with both the Shc SH 2 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 . . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| In this report , using a constitutively activated Ret TK form , Ret ptc 2 , we demonstrate that the MEN 2B as the activated WT Ret TK binds to several SH 2 signalling proteins such as Shc , Grb 2 , Phospholipase Cgamma , Crk and Nck . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Shc and Enigma are both required for mitogenic signaling by Ret / ptc2 . ^^^ Because Shc interacts with MEN 2 forms of Ret , and because phosphorylation of Shc results in Grb 2 recruitment and subsequent signaling through Ras and Raf , the potential interaction between Ret / ptc2 and Shc was investigated . ^^^ The PTB domain of Shc also interacted with Ret / ptc2 at tyrosine 586 , and this association resulted in tyrosine phosphorylation of Shc . ^^^ Coexpression of chimeric proteins demonstrated that mitogenic signaling from Ret / ptc2 required both recruitment of Shc and subcellular localization by Enigma . ^^^ Because Shc and Enigma interact with the same site on a Ret / ptc2 monomer , dimerization of Ret / ptc2 allows assembly of molecular complexes that are properly localized via Enigma and transmit mitogenic signals via Shc . . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK : substitution of the tyrosine 1062 of Ret , the Shc binding site , for phenylalanine abrogates ERK but not JNK activation . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Moreover , it turned out that tyrosine 1062 regulates the activity of both MEN 2A Ret and MEN 2B Ret and represents a binding site for the Shc adaptor protein . . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| However , in intact cells , the interaction of Grb 2 with the two short and long Ret isoforms expressed separately is of similar strength , thus suggesting that Ret short isoform interaction with Grb 2 could be mediated not only by Shc but also by a molecule that binds preferentially to this isoform . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| A tyrosine residue at position 1062 is an intracytoplasmic docking site that enables RET to recruit several signalling molecules , including the Shc adaptor protein . ^^^ We now report that both HSCR mutations impair the fixation of Shc to RET and consequently prevent its phosphorylation . ^^^ Finally , we provide evidence that these effects are partly mediated via the disruption of the RET / Shc interaction . ^^^ Collectively , these results demonstrate that HSCR can be ascribed to mutations of RET which interfere with the binding of transduction effectors , such as Shc , and further provide a biochemical explanation for the phenotype of patients carrying a homozygous mutation at codon 1061 . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| In these cells , the constitutive tyrosine phosphorylation of ret / ptc1 , of the transducing adaptor protein shc and of a series of co immunoprecipitated peptides became much reduced , as demonstrated by immunoprecipitation / Western blot analyses . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Ret oncogene signal transduction via a IRS 2 / PI 3 kinase / PKB and a SHC / Grb 2 dependent pathway : possible implication for transforming activity in NIH3T3 cells . ^^^ Moreover , Ret 9bp induces phosphorylation of SHC resulting in growth factor receptor binding protein 2 ( Grb 2 ) binding and activation of the mitogen activating protein ( MAP ) kinase pathway . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Recently , it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS / mitogen activated protein kinase ( MAPK ) and phosphatidylinositol 3 kinase ( PI 3 K ) / AKT signaling pathways . ^^^ In response to GDNF stimulation , SHC bound to GAB 1 and GRB 2 adaptor proteins as well as RET , and SHC and GAB 1 were highly phosphorylated on tyrosine . ^^^ The complex formation consisting of SHC , GAB 1 and GRB 2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine . ^^^ These results suggested that the RAS and PI 3 K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| RET dimerization and its complex formation with Shc and Grb 2 adaptor proteins were detected in tumor tissues . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Phosphorylated Y 1062 is part of a Ret multiple effector docking site that mediates recruitment of the Shc adapter and of phosphatidylinositol 3 kinase ( PI3K ) . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| The insulin receptor substrate ( IRS ) 1 recruits phosphatidylinositol 3 kinase to Ret : evidence for a competition between Shc and IRS 1 for the binding to Ret . ^^^ Finally , we show that Shc , which was previously identified as another ligand of Y 1062 of Ret , competes with IRS 1 for the binding to Ret pY 1062 . ^^^ The alternative binding of Shc and IRS 1 to Ret pY 1062 can be a system to modulate the activation of different intracellular signaling pathways and to elicit different biological responses following Ret activation . . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| 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 GRB 2 and GAB 1 proteins , SNT / FRS2 was associated with GRB 2 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 ( PI 3 K ) / AKT pathway . ^^^ 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 . . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Complex formation between RET and FRS 2 is mediated by binding of the phosphotyrosine binding domain of FRS 2 to pY 1062 , a residue in RET that also functions as a binding site for Shc . ^^^ However , overexpression of FRS 2 but not Shc potentiates mitogen activated protein ( MAP ) kinase activation by RET oncoproteins . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Effects of RET / PTC on DNA synthesis and apoptosis did not require direct interaction of the oncoprotein with either Shc or phospholipase Cgamma . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| A constitutive complex of Grb 2 and Cbl could be recruited to both receptor isoforms via docking of Shc to phosphorylated Tyr 1062 in RET . ^^^ Cbl complex decreased the turnover and prolonged the half life of RET 9 , thus ascribing a previously unknown negative role to the Shc adaptor molecule . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| RAI ( ShcC / N Shc ) dependent recruitment of GAB 1 to RET oncoproteins potentiates PI 3 K signalling in thyroid tumors . ^^^ RAI , also named ShcC / N Shc , one of the members of the Shc proteins family , is a substrate of the RET receptor tyrosine kinase . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| To elucidate the molecular basis for signaling specificity of GDNF mediated RET signaling in kidney development , we characterized mice that exclusively express either the human RET 9 or RET 51 isoform , or express these isoforms with individual mutations in docking tyrosines for PTB and SH 2 domain containing adaptors Src ( Y 981 ) , PLCgamma ( Y 1015 ) , and Shc ( Y 1062 ) . ^^^ |
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| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| Signaling downstream of Ret is thus modified through a mechanism that involves the adaptor protein Shc as well as ERK , eventually blocking Akt activation . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| This results in a significant decrease of RET induced Shc and extracellular signal regulated kinase 1 / 2 phosphorylation levels . ^^^ |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P07949 and P29353 |
Pubmed |
SVM Score :0.0 |
| NA |
|