Pubmed abstracts for Protein-Protein Interaction search result :


Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.50540001
When the Ash binding motif peptide of the epidermal growth factor receptor was used to detect complexes formed with Ash in vivo , 180 kDa , 150 kDa , 110 kDa , 100 kDa and 65 kDa proteins were also bound ; this shows that these proteins form complexes with Ash in brain . 0.50540001^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :1.8016342
These analyses reveal a hierarchy of interactions between Grb 2 and Shc with the EGFR and indicate that Grb 2 can bind the tyrosine phosphorylated EGFR directly , as well as indirectly via Shc . . 1.8016342^^^ From these studies , we concluded that Grb 2 binds directly to the EGFR at Y 1068 , to a lesser extent at Y 1086 , and indirectly at Y 1173 . 0.92763176^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.51056318
The EGFR is coupled to the Ras signalling pathway by interaction with the adaptor protein Grb 2 , and Sos , a Ras GDP GTP exchange factor . 0.51056318^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.54476411
A human protein , GRB 2 , was identified by its ability to associate with the activated human epidermal growth factor receptor ( hEGFR ) . 0.54476411^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.95905842
HRG also induced the association of GRB 2 with tyrosine phosphorylated p185c erbB 2 , p180erbB 4 and SHC . 0.95905842^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.604431
Because Ras activation by EGF involves EGF stimulated association of EGF R with Grb 2 , the EGF R was immunoprecipitated and a Western blot was probed for Grb 2 . 0.604431^^^ As expected we found that EGF stimulated an association of EGF R with Grb 2 , PRL , however , blocked this association . 0.52624595^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.52819695
Here , we showed that a synthetic phosphopeptide encompassing the autophosphorylation site 1068 of EGFR formed a complex with endogenous Grb 2 after this peptide was delivered into intact cells by a cell permeable peptide import technique . 0.52819695^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.69396105
In both cases , ErbB 1 coupled to the adaptor protein Shc , but only when activated by EGF was it able to interact with Grb 2 . 0.69396105^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.69673711
Dephosphorylation of the tyrosine phosphorylated ErbB proteins abolished their association with both Grb 2 and Shc , suggesting a tyrosine phosphorylation dependent interaction . 0.69673711^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.70875921
In addition , UCS15A had no effect on the SH 2 mediated interaction between Grb 2 and activated Epidermal Growth Factor receptor . 0.70875921^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.85203083
The adaptor protein Grb 2 ( growth factor receptor binding protein 2 ) binds to EGFR , which leads to activation of Ras MAPK ( mitogen activated protein kinase ) cascade . 0.85203083^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Wiskott Aldrich syndrome protein is associated with the adapter protein Grb 2 and the epidermal growth factor receptor in living cells . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
After binding to EGFR , PTP1B becomes tyrosine phosphorylated at Tyr 66 , a site that conforms to the consensus binding sequence for the Src homology 2 ( SH 2 ) domains of the adapter protein Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Combined cell lysates were affinity purified over the SH 2 domain of the adapter protein Grb 2 ( GST SH 2 fusion protein ) that specifically binds phosphorylated EGFR and Src homologous and collagen ( Shc ) protein . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
A tyrosine phosphorylated peptide of the epidermal growth factor receptor specifically retrieved the Src homology domain ( SH ) 2 and SH 3 domain containing adapter protein Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The interaction of the activated epidermal growth factor ( EGF ) receptor ( EGFR ) with the Src homology 2 ( SH 2 ) domain of Grb 2 ( growth factor receptor bound protein 2 ) initiates signalling through Ras and mitogen activated protein kinase . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Nucleotide exchange stimulation by PE is prevented by PKC ( protein kinase C ) inhibition but not by EGFR [ EGF ( epidermal growth factor ) receptor ] blockade , despite the fact that EGFR inhibition aborts basal and PE induced Shc ( Src homology and collagen homology ) phosphorylation and Shc Grb 2 ( growth factor receptor bound protein 2 ) association . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
ASH bound in vitro to phosphotyrosine containing proteins , including activated epidermal growth factor receptor , the ASH SH 2 domain being responsible for the binding . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Saturation of the SH 2 domain of Grb 2 with the EGFR phosphopeptide was found not to affect its subsequent binding to the Sos peptide . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
SHC and GRB 2 are constitutively by an epidermal growth factor receptor with a point mutation in the transmembrane domain . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Although phosphorylated EGFR can bind to both Shc and Grb 2 , the predominant linkage was observed between EGFR and Shc . ^^^ Similarly , more Grb 2 was associated with Shc than with EGFR after EGF stimulation . ^^^ Immunoprecipitation of Shc from EGF stimulated cells removed almost all EGFR associated Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We have mapped GRB 2 , a signal transduction gene whose protein product is an essential component of the pathway between tyrosine kinases ( such as the epidermal growth factor receptor ) and downstream proteins ( such as Ras and Sos ) . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Recently activation of the ras signal transduction pathway by the EGFR has been shown to involve the Shc and Grb 2 proteins . ^^^ In this communication , we demonstrate that the Shc proteins are phosphorylated on tyrosine residues and are complexed with Grb 2 and the chicken EGFR following ligand activation of this receptor . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Northern blot analysis revealed that 7 / 19 breast cancer cell lines exhibited more than twofold overexpression of Grb 2 mRNA , with overexpression correlating with high expression of erbB receptors . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In addition , though certain signal transmitters , including Shc and GRB 2 , were recruited by both kinases , EGFR and ErbB 3 elicited tyrosine phosphorylation of distinct sets of intracellular substrates . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In contrast to the activated epidermal growth factor receptor that binds the GRB 2 Sos complex directly , activation of the insulin receptor results in the interaction of GRB 2 Sos with IRS 1 and Shc , thus linking the insulin receptor to Ras signaling pathways . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Furthermore , we have identified a short sequence motif ( YV / IN ) present in IRS 1 , EGFR and Shc , which specifically binds the SH 2 domain of GRB 2 with high affinity . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In response to calcium influx , Shc , Grb 2 , and Sos 1 inducibly associate with a 180 kDa tyrosine phosphorylated protein , which was determined to be the epidermal growth factor receptor ( EGFR ) . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
UV induces the formation of complexes between activated EGFR and SOS , Grb 2 , PLC gamma , and SHC that can be precipitated with antibodies to EGFR . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The data revealed new potential Grb 2 binding sites at Tyr 1114 ( epidermal growth factor receptor ( EGFR ) C tail ) ; Tyr 743 ( platelet derived growth factor receptor ( PDGFR ) insert region ) , Tyr 1110 from the E helix of the catalytic domain of insulin receptor ( IR ) , and Tyr 47 , Tyr 939 , and Tyr 727 in IRS 1 . ^^^ Tyr 1068 and 1086 from the C tail of EGFR , Tyr 684 from the kinase insert region of PDGFR , and Tyr 895 from IRS 1 were confirmed as major binding sites for the Grb 2 SH2 domain . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
However , in lymphocytes activated through the TCR , Cbl loses its ability to bind to Grb 2 precipitated either with anti Grb 2 antibody or with an immobilized tyrosine phosphopeptide , Y 1068 P , derived from the epidermal growth factor receptor . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Epidermal growth factor receptor targeting prevents uncoupling of the Grb 2 SOS complex . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The C terminal region of Sos binds an adaptor protein , Grb 2 , which in turn binds to activated receptors including the EGF receptor ( EGFR ) . ^^^ Therefore , we investigated whether the ability of Sos 1 to form complexes with Grb 2 and with the EGF receptor ( EGFR ) changes following EGF stimulation , as a possible mechanism for regulating Sos activity . ^^^ We find that following EGF stimulation , the Sos 1 protein associated with the EGFR is markedly less phosphorylated than the majority of the Sos 1 within the cell and there was reduced binding of Grb 2 with phosphorylated Sos 1 protein in a direct binding assay . ^^^ A time course analysis showed that Sos 1 dissociates from the EGFR more rapidly than does Grb 2 following EGF stimulation . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Enhanced tumorigenic behavior of glioblastoma cells expressing a truncated epidermal growth factor receptor is mediated through the Ras Shc Grb 2 pathway . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The Grb 2 SH2 domain binds to Tyr 1068 of EGFR and Tyr 317 of Shc while its SH 3 domains bind to mSos 1 . ^^^ Therefore , EGF treatment potentially results in the formation of several multimeric signaling complexes , including EGFR Grb 2 mSos1 , EGFR Shc Grb 2 mSos1 , and Shc Grb 2 mSos1 , linking the receptor to activation of the Ras GTPase . ^^^ An EGFR derived phosphopeptide bound Grb 2 with a KD of 0 . 7 microM , whereas the Shc derived phosphopeptide bound Grb 2 with a KD of 0 . 2 microM . ^^^ Grb 2 mSos1 bound to both EGFR and Shc derived phosphopeptides with higher affinities ( KD of 0 . 3 microM and 31 nM , respectively ) than Grb 2 alone . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Finally , the PKAI EGF R association occurs through the binding of RIalpha to the SH 3 domain ( s ) of Grb 2 adaptor protein , thus allowing the recruitment of the PKAI holoenzyme to the activated EGF R . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Tyrosine phosphorylation of EGF receptor ( EGFR ) , Shc , and phospholipase C gamma 1 ( PLC gamma ) , and growth factor receptor binding protein 2 ( Grb 2 ) coprecipitation with EGFR and Shc were analyzed by Western blotting . ^^^ Grb 2 binding to EGFR was suppressed , but EGF induced Shc tyrosine phosphorylation and Grb 2 association with Shc were not significantly decreased . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Competitive inhibition of substrate binding and mutagenesis experiments with EGFR / Ufo constructs revealed C terminal tyrosine 821 ( EILpYVNMDEG ) as a docking site for multiple effectors , namely PLCgamma , p 85 proteins , GRB 2 , c src and lck . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We now show that growth hormone stimulates tyrosine phosphorylation of the receptor for epidermal growth factor ( EGFR ) and its association with Grb 2 and at the same time stimulates MAP kinase activity in liver , an important target tissue of growth hormone . ^^^ Moreover , tyrosine at residue 1 , 068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb 2 binding sites stimulated by growth hormone via Jak 2 . ^^^ Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak 2 , thereby providing docking sites for Grb 2 and activating MAP kinases and gene expression , independently of the intrinsic tyrosine kinase activity of EGFR . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Stimulation of PDGFR ' s and EGFR ' s induced tyrosine phosphorylation of the Shc adaptor protein and its association with Grb 2 , suggesting a mechanism by which Ras may be activated in human malignant astrocytoma cells . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
This effect has been associated with reduced EGF induced EGF receptor ( EGFR ) tyrosine phosphorylation , Grb 2 association , and Ras activation . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
These studies therefore identify Grb 7 as an in vivo target of erbB 3 and erbB 4 and provide an underlying mechanism for the ability of erbB 3 to recruit Grb 7 and not Grb 2 , a property unique among erbB receptors . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We have shown that an interaction between EGFR and PKAI occurs through direct binding of the RI subunit to the Grb 2 adaptor protein . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
This fusion protein entered cells , formed a complex with phosphorylated EGF receptor ( EGFR ) , and inhibited EGF induced EGFR Grb 2 association and mitogen activated protein kinase activation . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We recently showed that GH mainly stimulated tyrosine phosphorylation of epidermal growth factor receptor and its association with Grb 2 , and concomitantly stimulated mitogen activated protein kinase activity in liver , a major target tissue . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Dominant negative forms of SHP 2 had no effect on EGF stimulated interaction of GRB 2 with EGFR or SHC , nor did they influence phosphorylation of SHC and SHC / EGFR association . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The arsenite induced tyrosine phosphorylation of Shc , enhancement of Shc and Grb 2 interactions , and activation of ERK were all drastically reduced by treatment of cells with either the general growth factor receptor poison suramin or the EGFR selective inhibitor tyrphostin AG 1478 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Immunoprecipitation / Western blot studies revealed that CCh stimulated tyrosine phosphorylation of the EGF receptor ( EGFr ) and increased co immunoprecipitation of the adapter proteins , Shc and Grb 2 , with the EGFr . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
This correlates with a specific inability to achieve high levels of p 66 ( SHC ) tyrosyl phosphorylation and association of p 66 ( SHC ) with GRB 2 , despite high levels of EGF receptor ( EGFR ) autophosphorylation . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In addition , 14 , 15 EET SI administration stimulated tyrosine phosphorylation of src homologous and collagen like protein ( SHC ) and association of SHC with both growth factor receptor binding protein ( GRB 2 ) and EGFR . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We now show that GH stimulated tyrosine phosphorylation of epidermal growth factor receptor ( EGFR ) and its association with Grb 2 , and concomitantly stimulated MAP kinase activity in liver , a major target tissue . ^^^ Moreover , by also using dominant negative JAK 2 and in vitro kinase assay , we demonstrated that tyrosine 1068 of EGFR was evidently one of the major phosphorylation and Grb 2 binding sites stimulated by GH via JAK 2 . ^^^ These data suggest that the role of EGFR in GH signalling is to be phosphorylated by JAK 2 , thereby providing docking sites for Grb 2 and activating MAP kinases and gene expression . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
At 50 nM , the peptidimer blocks selectively Grb 2 Sos complexation in ER 22 ( CCL 39 fibroblasts overexpressing epidermal growth factor receptor ) cellular extracts . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Although a selective EGFR kinase inhibitor completely abolished Ang 2 induced recruitment of Grb 2 to EGFR and markedly attenuated Ang 2 induced ERK activation , it had no effect on Ang 2 induced PYK 2 tyrosine phosphorylation or its association with c Src and Grb 2 . ^^^ These data suggest that the AT 1 receptor uses Ca2+ dependent PYK 2 to activate c Src , thereby leading to EGFR transactivation , which preponderantly recruits Grb 2 in rat VSMC . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Growth inhibition of breast cancer cells by Grb 2 downregulation is correlated with inactivation of mitogen activated protein kinase in EGFR , but not in ErbB 2 , cells . ^^^ Grb 2 is important for the transformation of fibroblasts by EGFR and ErbB 2 ; however , whether Grb 2 is also important for the proliferation of breast cancer cells expressing these RTKs is unclear . ^^^ Grb 2 inhibition led to MAP kinase inactivation in EGFR , but not in ErbB 2 , breast cancer cells , suggesting that different pathways might be used by EGFR and ErbB 2 to regulate breast cancer growth . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Accordingly , CGP 78850 blocks epidermal growth factor receptor ( EGFR ) Grb 2 and Shc Grb 2 interactions in living cells . ^^^ Moreover , our results demonstrate that , in cells overexpressing receptor tyrosine kinases , such as the EGFR , Grb 2 SH2 inhibitors induce expression of the cell cycle inhibitors p 21 ( Waf1 / Cip1 / CAP1 ) and p 27 ( Kip 1 ) and reverse transformation . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
AP 1510 treatment induced tyrosine phosphorylation of ErbB 1 and ErbB 2 homodimers and recruitment of Src homology 2 domain containing proteins ( Shc and Grb 2 ) . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Phosphorylated EGF R bound the adaptor protein , Grb 2 , and the EGF R selective tyrphostin , AG 1478 , blocked the C5b 9 induced ERK 2 phosphorylation , [ ( 3 ) H ] AA release , and PGE ( 2 ) production by 45 to 65 % , supporting a functional role for EGF R kinase in mediating the activation of these pathways . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
OA induced EGFR autophosphorylation triggered EGFR signaling pathway activation ( as assessed through coimmunoprecipitation of SH 2 proteins such as SHC , GRB 2 , and SHP 2 ) and subsequent p42 / p44 mitogen activated protein kinase ( as shown by the use of EGFR deficient B82L and EGFR transduced B82LK ( + ) cell lines ) . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
By contrast , Shc and Grb 2 were inducibly associated with the EGFR in response to EGF stimulation of glioma cells . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The presence of Grb 2 , Shc , and Sos in this complex implicates Ras in ligand independent signaling by these oncogenic epidermal growth factor receptor mutants . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The enhanced activation of EGFR by the tethered form of TGFalpha was reflected by higher activation of Grb 2 , SHC and Erk downstream mediators of EGF receptor signaling . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
EGFR truncation had no significant effect on AR binding to receptor but did result in defective GRB 2 adaptor function . ^^^ In contrast , EGFR truncation did not impair EGF mitogenic signaling , and in c ' 1000 cells EGF was able to stimulate the association of ErbB 2 with GRB 2 and SHC . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We demonstrate in vivo , that cbl b , like c cbl , is phosphorylated and recruited to the EGFR upon EGF stimulation and both cbl proteins can bind to the Grb 2 adaptor protein . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
To examine the affinity of the phage derived peptides for GRB 2 , we set up a radioligand competition binding assay based on immobilized GRB 2 and radiolabelled autophosphorylated EGFR ICD as the radioligand . ^^^ We also demonstrated the ability of the peptides to block the binding of the GRB 2 SH2 domain to EGFR in a mammalian cell based binding assay . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Two adaptor molecules , Grb 2 and Shc , have been implicated in the extracellular signal regulated kinase ( ERK ) activation by receptor tyrosine kinases such as the epidermal growth factor receptor ( EGFR ) . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Coimmunoprecipitation studies demonstrated that both EGF and Cpd 5 induced tyrosine phosphorylation of EGFR was associated with increased amounts of adapter proteins Shc and Grb 2 , and the Ras GTP GDP exchange protein Sos , indicating the formation of functional EGFR complexes . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In the A 549 human adenocarcinoma cell line dexamethasone inhibited epidermal growth factor ( EGF ) stimulated cytosolic PLA ( 2 ) ( cPLA ( 2 ) ) activation and AA release by blocking the recruitment of Grb 2 to the activated EGF receptor ( EGF R ) through a glucocorticoid receptor ( GR ) dependent ( RU 486 sensitive ) , transcription independent ( actinomycin insensitive ) , mechanism . ^^^ The dexamethasone induced block of Grb 2 recruitment was parallelled by changes in phosphorylation status and subcellular localization of lipocortin 1 ( LC 1 ) and an increase in the amount of the tyrosine phosphoprotein co localized with EGF R . ^^^ Our results point to an unsuspected rapid effect of glucocorticoids , mediated by occupation of GR but not by changes in gene transcription , which is brought about by competition between LC 1 and Grb 2 leading to a failure of recruitment off signalling factors to EGF R . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We found that the signaling pathway involves the activation of epidermal growth factor receptor ( EGFR ) kinase , activation of the adaptor proteins Shc and Grb 2 , and the small G protein Ras . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
SP induced formation of an activated EGFR complex containing the adapter proteins SHC and Grb 2 , but not c Src . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In OVCA 433 human ovarian carcinoma cells , ET 1 caused phosphorylation of the epidermal growth factor receptor ( EGF R ) that was accompanied by phosphorylation of Shc and its recruitment complexed with Grb 2 . ^^^ Specific inhibition of EGF R kinase activity by tyrphostin AG 1478 prevented ET 1 induced transactivation of the EGF R , as well as Shc phosphorylation and recruitment with Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The interaction of activated epidermal growth factor receptor ( EGFR ) with the Src homology 2 ( SH 2 ) domain of the growth factor receptor binding protein Grb 2 initiates signaling through Ras and mitogen activated protein kinase ( MAP kinase ) [ 1 , 2 ] . ^^^ To analyze the spatiotemporal regulation of EGFR Grb 2 interactions in living cells , we have combined imaging microscopy with a modified method of measuring fluorescence resonance energy transfer ( FRET ) on a pixel by pixel basis using EGFR fused to cyan fluorescent protein ( CFP ) and Grb 2 fused to yellow fluorescent protein ( YFP ) . ^^^ Efficient energy transfer between CFP and YFP should only occur if CFP and YFP are less than 50A apart , which requires direct interaction of the EGFR and Grb 2 fused to these fluorescent moieties [ 3 ] . ^^^ Stimulation by EGF resulted in the recruitment of Grb 2 YFP to cellular compartments that contained EGFR CFP and a large increase in FRET signal amplitude . ^^^ In particular , FRET measurements indicated that activated EGFR CFP interacted with Grb 2 YFP in membrane ruffles and endosomes . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Transient expression of Vav in 293T and NIH 3T3 cells demonstrated that ligand stimulation of several RPTKs ( epidermal growth factor receptor [ EGFR ] , Ros , insulin receptor [ IR ] , and insulin like growth factor 1 receptor [ IGFR ] ) led to tyrosine phosphorylation of Vav 3 and its association with the receptors as well as their downstream signaling molecules , including Shc , Grb 2 , phospholipase C ( PLC gamma ) , and phosphatidylinositol 3 kinase . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The phosphorylation of EGFR and c met by VK ( 3 ) appeared to be functional , because these were coimmunoprecipitated with growth factor receptor bound protein 2 ( Grb 2 ) and SOS 1 antibody . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We show that a substantial fraction of tyrosine phosphorylated epidermal growth factor receptor ( EGFR ) and Shc , Grb 2 and Cbl after internalization relocates from early endosomes to compartments which are negative for the early endosomes , recycling vesicle markers EEA 1 and transferrin in EGF stimulated cells . ^^^ Co immunoprecipitations showed EGFR in complex with both Shc , Grb 2 and Cbl . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Some molecules , such as Grb 2 , were primarily found associated with surface EGFR , whereas others , such as Eps 8 , were found only with intracellular receptors . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Recruitment of the class 2 phosphoinositide 3 kinase C2beta to the epidermal growth factor receptor : role of Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
GRB 2 is most well known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of RAS and its downstream kinases , ERK 1 , 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Tyrosine phosphorylation of Grb 2 by Bcr / Abl and epidermal growth factor receptor : a novel regulatory mechanism for tyrosine kinase signaling . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In support of this hypothesis , overexpression of the EGFR adaptor protein Grb 2 increased cell proliferation and restored EGF induced mitosis . . ^^^ Decreased mitogenic response to epidermal growth factor in human squamous cell carcinoma lines overexpressing epidermal growth factor receptor owing to limiting amounts of the adaptor protein Grb 2 : rescue by retinoic acid treatment . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Ang 2 also increased the association of the adaptor protein Grb 2 with the EGF R . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Ligand induced desensitization of the epidermal growth factor receptor ( EGFR ) is controlled by c Cbl , a ubiquitin ligase that binds multiple signaling proteins , including the Grb 2 adaptor . ^^^ The underlying mechanism seems to involve recruitment of a Grb 2 c Cbl complex to Grb 2 specific docking sites of EGFR , and concurrent acceleration of receptor ubiquitylation and desensitization . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
This resulted in increased binding of another adaptor protein Grb 2 to the Src EGFR complex and the subsequent activation of Ras and MAPKs . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Surprisingly , EGF and TGF alpha induced full activation of MAPK in duration and intensity and stimulated association of the EGFR with Shc and Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Role of Grb 2 in EGF stimulated EGFR internalization . ^^^ Grb 2 is an adaptor molecule that couples membrane receptors such as the epidermal growth factor receptor ( EGFR ) to intracellular signaling pathways . ^^^ To gain insight into the trafficking pathways followed by these molecules after activation by EGF , we visualized Grb 2 and EGFR fused to GFP spectral variants in single live cells . ^^^ In nonstimulated cells , Grb 2 YFP was primarily localized diffusely in the cytoplasm , whereas EGFR CFP was found on the plasma membrane and in endocytic structures localized in the perinuclear area . ^^^ Within 1 minute of EGF stimulation , Grb 2 redistributed to the plasma membrane where it bound EGFR CFP in an SH 2 dependent manner . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Introduction of a mutation that results in failure to bind Grb 2 abrogates the ability of Sf Stk to induce colonies in response to Friend virus , while the Grb 2 binding site from EGFR restores this response . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Irradiation of keratinocytes increases the phosphorylation of EGFR on tyrosine residues Y 845 , Y 992 , Y 1045 , Y 1068 , Y 1086 , Y 1148 , and Y 1173 above the basal levels and leads to the increased recruitment of the adaptor proteins Grb 2 and ShcA and of a p 55 form of the regulatory subunit of the phosphatidylinositide 3 kinase to the UVB activated EGFR . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
One of the critical intracellular signal transduction pathways involves the binding of the Grb 2 SH2 domain to the phosphotyrosine ( pTyr ) motifs on growth factor receptors , such as epidermal growth factor receptor ( EGFR ) and erbB 2 , leading to downstream activation of the oncogenic Ras signaling pathway . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Epidermal growth factor ( EGF ) stimulates recruitment of RN tre to the EGF receptor ( EGFR ) in a Grb 2 dependent manner . ^^^ Grb 2 and the EGFR are internalized and co localized in endocytic vesicles in response to EGF . ^^^ These results 1 ) suggest that the ability of RN tre to inhibit internalization of the EGFR requires Grb 2 mediated binding to the receptor and 2 ) identify Grb 2 as a critical regulator of Rab 5 and EGFR endocytosis . . ^^^ Endocytosis of epidermal growth factor receptor regulated by Grb 2 mediated recruitment of the Rab 5 GTPase activating protein RN tre . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
We found no evidence for ALPs acting via G protein coupled receptors and / or transactivation of EGFRs , as determined by calcium mobilization , EGFR phosphorylation and Grb 2 binding assays . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Stimulation of the epidermal growth factor receptor ( EGFR ) in HaCaT cells enhances the level of EGFR associated PAK 1 and Grb 2 , although the PAK 1 Grb2 association is itself independent of this stimulation . ^^^ A cell permeant TAT tagged peptide encompassing the second proline rich SH 3 binding domain of PAK 1 simultaneously blocked Grb 2 and activated EGFR association with PAK 1 , in vitro and in vivo , indicating that Grb 2 mediates the interaction of PAK 1 with the activated EGFR . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The double mutant ( DM ) protein identified the epidermal growth factor receptor ( EGFR ) , the Grb 2 binder 1 , and three other , as yet unidentified , phosphotyrosyl proteins as candidate physiological substrates . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Immunoprecipitation / Western blot studies revealed that BK stimulated tyrosine phosphorylation of EGFR , its association with an adapter molecule Grb 2 , and complex formation between Grb 2 and the adapter protein Shc . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Quantitative analysis of colocalization of EGF rhodamine conjugate and coated pits labeled with yellow fluorescent protein tagged beta 2 subunit of clathrin adaptor complex AP 2 revealed that EGFR mutants lacking Grb 2 binding sites do not efficiently enter coated pits . ^^^ The depletion of Grb 2 from PAE as well as HeLa cells expressing endogenous EGFRs by RNA interference substantially reduced the rate of EGFR internalization through clathrin dependent pathway , thus providing the direct evidence for the important role of Grb 2 in this process . ^^^ Overexpression of Grb 2 mutants , in which the SH 3 domains were either deleted or inactivated by point mutations , significantly inhibited EGFR internalization in both PAE and HeLa cells . ^^^ These findings indicate that Grb 2 , in addition to its key function in signaling through Ras , has a major regulatory role at the initial steps of EGFR internalization through clathrin coated pits . ^^^ Furthermore , the EGFR mutant lacking Grb 2 binding sites did not efficiently recruit c Cbl and was not polyubiquitinated . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Ligand regulated trafficking of the EGFR is mediated by a series of motifs distributed through the cytoplasmic domain of the receptor that are exposed by a combination of activation mediated conformation changes and the binding of proteins such as Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Molecular dynamics , free energy , and SPR analyses of the interactions between the SH 2 domain of Grb 2 and ErbB phosphotyrosyl peptides . ^^^ We studied the interactions between the SH 2 domain of growth factor receptor binding protein 2 ( Grb 2 ) and ErbB receptor derived phosphotyrosyl peptides using molecular dynamics , free energy calculations , and surface plasmon resonance ( SPR ) analysis . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The tyrosine phosphorylated EGFR was immunoprecipitated together with GRB 2 and tyrosine phosphorylated Shc , indicating that transactivated EGFR is able to generate downstream signals . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
These data suggest that the binding of Cbl to epidermal growth factor receptor through Grb 2 is necessary and sufficient for Cbl function during clathrin mediated endocytosis . ^^^ Overexpression of c Cbl mutants that are capable of Grb 2 binding but defective in linker / RING finger domain function severely inhibited epidermal growth factor receptor internalization . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The membranes were probed with antibody against human growth factor receptor binding protein ( Grb 2 ) to detect the association of this Ras MAPK upstream adaptor protein to EGFR . ^^^ Immunoblots showed that Grb 2 was co immunoprecipitated with EGFR after EGF stimulation . ^^^ CONCLUSIONS : 1 ) Association of Grb 2 to EGFR in BxPC 3 induced by EGF in the presence of Erbitux indicates an alternate pathway of Ras MAPK activation , which may be related with the tumor resistance to treatment ; 2 ) transactivation of EGFR downstream Ras MAPK pathway by FGF contributes the resistance to treatment ; and 3 ) downregulation of EGFR may increase the response to therapy . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
These growth factors , most notably EGF , trigger cell proliferation via signal transduction pathways involving EGF R , adapter proteins ( Grb 2 , Shc and Sos ) , Ras , Raf 1 and MAP ( Erk1 / Erk2 ) kinases , which , after translocation to nuclei , activate transcription factors and cell proliferation . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Immunocytochemistry on kidney sections using specific antibodies against TGF alpha , HB EGF , EGFr , IGF 1Rbeta , Grb 2 , and phospho p44 / 42 MAP kinase ( ERK1 / 2 ) revealed a significantly higher staining of these molecules 3 to 72 hours after dosing , indicating up regulation of the ERK pathway . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Using this technique , we have studied the process of early signal transduction of epidermal growth factor ( EGF ) in single molecules : binding of EGF to its receptor ( EGFR ) on the cell surface , dimerization of EGFR induced by binding of EGF , fluctuation of the structure of EGFR clusters , activation of EGFR through tyrosine phosphorylations on its cytoplasmic domain , and recognition of activated EGFR by a cytoplasmic adaptor protein , Grb 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Epidermal growth factor receptor ( EGFR ) tyrosine phosphorylation and recruitment of its adaptor proteins , Shc and Grb 2 , to EGFR were detected by immunoprecipitation and Western blot analysis . ^^^ After arsenical treatment , Shc immunoprecipitates contained coprecipitated EGFR and Grb 2 , suggesting that both arsenicals induce the assembly of EGFR Shc Grb 2 complexes . ^^^ CONCLUSIONS : Our data indicate that both arsenite and arsenate activate the EGFR Shc Grb 2 MEK1 / 2 ERK1 / 2 signalling cascade in NHEK . . ^^^ Epidermal growth factor receptor ( EGFR ) tyrosine phosphorylation and recruitment of its adaptor proteins , Shc and Grb 2 , to EGFR were detected by immunoprecipitation and Western blot analysis . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Moreover , a series of recent studies has shown that the highly conserved cytoplasmic tail of MUC 1 interacts specifically with a series of important signal transducing molecules including beta catenin , Grb 2 and erbB family members . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Thus , CALM is the second protein besides Grb 2 that appears to play a specific role in EGFR endocytosis . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Ligand binding causes the EGF receptor ( EGFR ) to become ubiquitinated by Cbl upon association with the adaptor protein Grb 2 . ^^^ We have investigated the role of ubiquitin and Grb 2 in ligand induced endocytosis of the EGFR . ^^^ Grb 2 with point mutations in both SH 3 domains inhibited recruitment of the EGFR to clathrin coated pits , in a Ras independent manner . ^^^ We propose that Grb 2 mediates transient anchoring of the EGFR to an Eps 15 containing molecular complex at the rim of coated pits and that Cbl induced ubiquitination of the EGFR allows relocation of EGFR from the rim to the center of clathrin coated pits . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Ubiquitination of the EGFR was in HeLa cells inhibited both upon overexpressing the N terminal part of Cbl and upon overexpressing a double mutant Grb 2 incapable of interacting with Cbl and thereby being incapable of indirectly recruiting Cbl to the EGFR . ^^^ Collectively , these data suggest that the ubiquitination resulting from direct binding of Cbl to pTyr 1045 of the EGFR is critical for lysosomal sorting of the EGFR in contrast to ubiquitination resulting from Grb 2 mediated binding of Cbl to the EGFR . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
In fibroblasts , survival signals emanating from the epidermal growth factor receptor appear to be PKB dependent , and this activation depends on the C terminal SH 3 domain of Grb 2 , likely through the interaction of Grb 2 with Gab1 . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Knockdown of growth factor receptor binding protein 2 ( Grb 2 ) by RNA interference strongly inhibits clathrin mediated endocytosis of the epidermal growth factor receptor ( EGFR ) . ^^^ To gain insights into the function of Grb 2 in EGFR endocytosis , we have generated cell lines in which endogenous Grb 2 was replaced by yellow fluorescent protein ( YFP ) tagged Grb 2 expressed at the physiological level . ^^^ In these cells , Grb 2 YFP fully reversed the inhibitory effect of Grb 2 knockdown on EGFR endocytosis and , moreover , trafficked together with EGFR during endocytosis . ^^^ However , EGFR endocytosis was rescued in Grb 2 depleted cells by chimeric proteins consisting of the Src homology ( SH ) 2 domain of Grb 2 fused to c Cbl . ^^^ The `` knockdown and rescue ' ' analysis revealed that the expression of Cbl Grb2 / SH2 fusions containing RING finger domain of Cbl restores normal ubiquitylation and internalization of the EGFR in the absence of Grb 2 , consistent with the important role of the RING domain in EGFR endocytosis . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
To elucidate the downstream signaling in the PC9 / ZD cellular machinery , complex formation between EGFR and its adaptor proteins GRB 2 , SOS , and Shc was examined . ^^^ A marked reduction in the GRB 2 EGFR complex and absence of SOS EGFR were observed in PC 9 / ZD cells , even though the protein levels of GRB 2 and SOS in PC 9 and PC 9 / ZD cells were comparable . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The effector pathway from the EGFR to PI3K in these nontransformed cells included the adaptor Grb 2 , the docking protein Gab 1 , and the phosphatase Shp 2 . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The model includes EGF , EGFR , the adapter proteins Grb 2 and Shc , and the guanine nucleotide exchange factor Sos , which is activated through EGF induced formation of EGFR Grb 2 Sos and EGFR Shc Grb 2 Sos assemblies at the plasma membrane . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
All of the truncation mutants exhibit greatly reduced binding to activated EGF R and lack proline rich sequences that mediate direct Cbl association with SH 3 proteins such as Grb 2 , yet a subset of mutants collectively enhances EGF R ubiquitination , downregulation , and degradation . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
These contained EGF , EGFR , clathrin , and Grb 2 but not the TfR . ^^^ Our data demonstrate that EGFR induced signaling and Grb 2 are essential for formation of clathrin coated pits accommodating the EGFR , while activation of MAPK and PI3K is not required . . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The phosphorylated ErbB 2 in CACO 2 cells recruits the cytoplasmic adaptor protein Grb 2 , consistent with previous studies showing phosphotyrosine 1139 to be a Grb 2 binding site . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
EGFR and ErbB 4 had several docking sites for Grb 2 , while ErbB 3 was characterized by six binding sites for PI3K . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
Ubiquitination of EGFR is mediated by the ubiquitin ligase Cbl , being recruited to the EGFR both directly and indirectly through association with Grb 2 . ^^^ In the present study , we have investigated the localization of EGFR , Cbl and Grb 2 with respect to coated and non coated domains of the endosomal membrane and to vesicles within MVBs . ^^^ Both EGFR , Grb 2 , and Cbl were concentrated in coated domains of the limiting membrane before translocation to inner vesicles of MVBs . ^^^ While almost all Hrs was in clathrin positive coats , EGFR and Grb 2 in coated domains only partially colocalized with Hrs and clathrin . ^^^ The extent of colocalization of EGFR and Grb 2 with Hrs and clathrin varied with time of incubation with EGF . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
The protein encoded by this cDNA , Grb 3 3 , did not bind to phosphorylated epidermal growth factor receptor ( EGFR ) but retained functional SH 3 domains and inhibited EGF induced transactivation of a Ras responsive element . ^^^
Interacting proteins: P62993 and P00533 Pubmed SVM Score :0.0
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