| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.68105601 |
| We have shown previously that Cbl binds to ZAP 70 through its N terminal tyrosine kinase binding ( TKB ) domain . 0.68105601^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.69772419 |
| Furthermore , the association of Zap 70 with c Cbl was shown to be induced by T cell receptor stimulation , implying that it required posttranslational modification of one or both of these products . 0.69772419^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.65695223 |
| These results identify a potential Cbl PTB domain dependent role for Cbl in the negative regulation of ZAP 70 and predict potential Cbl PTB domain binding sites on other protein tyrosine kinases known to interact with Cbl . . 0.65695223^^^ |
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| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.67465562 |
| This finding is supported by studies showing that c Cbl interacts directly with a negative regulatory tyrosine in ZAP 70 , and that the levels of tyrosine phosphorylated ZAP 70 and numerous other proteins are increased in TCR stimulated thymocytes from c Cbl deficient mice . 0.67465562^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.667028 |
| Although the exact mechanism of interaction between these molecules has not been fully defined , it has been generally accepted that Crk , ZAP 70 , and p 85 interact with tyrosine phosphorylated Cbl , which serves as a major scaffold protein in activated T lymphocytes . 0.667028^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Similarly , Syk and SykB , but not Zap 70 , caused prominent tyrosine phosphorylation of p 120 ( c ) cbl in COS 1 cells . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| First , Cbl deficiency markedly up regulated the activity of ZAP 70 and mitogen activated protein kinases . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| A novel phosphotyrosine binding domain in the N terminal transforming region of Cbl interacts directly and selectively with ZAP 70 in T cells . ^^^ Recently , we and others have reported the activation dependent association of Cbl with the Syk and ZAP 70 tyrosine kinases through presently undefined mechanisms . ^^^ Here , we show that in vitro Cbl N ( amino acids 1 357 ) but not Cbl C ( amino acids 358 906 ) binds to ZAP 70 in a T cell activation dependent manner . ^^^ A point mutation in Cbl N , G306E , corresponding to a loss of function mutation in the Caenorhabditis elegans Cbl homologue , SLI 1 , severely compromised Cbl N / ZAP 70 binding . ^^^ Cbl N / ZAP 70 binding was direct and phosphotyrosine dependent , thus identifying a phosphotyrosine binding domain within the transforming region of Cbl . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| We further extend the studies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap 70 associated with TCRzeta isoforms and differential phosphorylation of p 120 proto oncogene c Cbl . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Based on genetic evidence that the Caenorhabditis elegans Cbl homolog , SLI 1 , functions as a negative regulator of the LET 23 receptor tyrosine kinase and our demonstration that Cbl ' s evolutionarily conserved N terminal transforming region ( Cbl N ; residues 1 to 357 ) harbors a phosphotyrosine binding ( PTB ) domain that binds to activated ZAP 70 tyrosine kinase , we examined the possibility that oncogenic Cbl mutants may activate mitogenic signaling by deregulating cellular tyrosine kinase machinery . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Tissue hyperplasia and enhanced T cell signalling via ZAP 70 in c Cbl deficient mice . ^^^ Our findings demonstrate critical roles for c Cbl in hemopoiesis and in controlling cellular proliferation and signalling by the Syk / ZAP 70 family of protein kinases . . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| In addition to Zap 70 , the 3BP2 SH 2 domain associated in vitro with LAT , Grb 2 , PLCgamma 1 , and Cbl from activated T cell lysates . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| A direct interaction between the adaptor protein Cbl b and the kinase zap 70 induces a positive signal in T cells . ^^^ One of the prominent substrates for these kinases is the adaptor protein Cbl [ 3 ] and recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap 70 [ 4 ] [ 5 ] . ^^^ A loss of function mutation in Cbl b disrupted the interaction between Cbl b and Zap 70 and nearly completely abrogated the Cbl b mediated activation of NFAT . ^^^ Unlike the proposed role of Cbl as a negative regulator , our results suggest that the Cbl homologue Cbl b has a positive role in T cell signaling , most likely via a direct interaction with the upstream kinase Zap 70 . . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Structure of the amino terminal domain of Cbl complexed to its binding site on ZAP 70 kinase . ^^^ In T cells , Cbl N binds to the tyrosine phosphorylated inhibitory site of the protein tyrosine kinase ZAP 70 . ^^^ Here we describe the crystal structure of Cbl N , both alone and in complex with a phosphopeptide that represents its binding site in ZAP 70 . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| The oncogenic 70Z Cbl mutation blocks the phosphotyrosine binding domain dependent negative regulation of ZAP 70 by c Cbl in Jurkat T cells . ^^^ T cell receptor ( TCR ) engagement results in the activation of Src family ( Lck and Fyn ) and ZAP 70 protein tyrosine kinases , leading to tyrosine phosphorylation of multiple cellular substrates including the complex adapter protein c Cbl . ^^^ Cbl associates via its phosphotyrosine binding ( PTB ) domain to the ZAP 70 pY 292 negative regulatory phosphotyrosine . ^^^ Here , we demonstrate that kinase dead but not wild type forms of Fyn , Lck , and ZAP 70 block 70Z Cbl mediated NFAT activation . ^^^ Moreover , 70Z Cbl does not upregulate NFAT in the ZAP 70 deficient P 116 Jurkat T cell line . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| The involvement of the proto oncogene p 120 c Cbl and ZAP 70 in CD 2 mediated T cell activation . ^^^ The inhibitory effect of c Cbl depended upon its N terminal phosphotyrosine binding domain , the domain that has been shown to be required for inhibition of the Syk / ZAP 70 family kinases . ^^^ Thus , CD 2 mediated NF AT transcriptional activity appears to depend upon ZAP 70 / Syk kinases and to be negatively regulated by c Cbl . . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| After stimulation of the T cell receptor ( TCR ) , the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP 70 become phosphorylated and plausibly function as docking sites for Cbl and Vav 1 , respectively . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Upon CD 3 CD4 ligation , TCR zeta phosphorylation , ZAP 70 recruitment to the p21 / p23 TCR zeta phosphoisomers , ZAP 70 phosphorylation , as well as p 56 ( lck ) , c Cbl and Slp 76 phosphorylation , were all markedly increased in CD45R0 ( + ) compared with CD45RBC ( + ) cells . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| SLAP 2 interacts with Cbl in vivo in a phosphorylation independent manner and with ZAP 70 and T cell receptor zeta chain upon T cell receptor activation . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Finally , analysis of a ZAP 70 deficient T cell line revealed that Cbl inhibited Lck dependent mitogen activated protein kinase activation , and an intact Cbl RING finger domain was required for this functional effect . ^^^ Our results demonstrate a direct , ubiquitination dependent , negative regulatory role of Cbl for Lck in T cells , independent of Cbl mediated regulation of ZAP 70 . . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Furthermore , FcR nonbinding anti CD 3 mAbs induced tyrosine phosphorylation of the Fyn substrate Cbl , but not the ZAP 70 substrate linker for activation of T cells . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Binding of SLAP 2 to both p 72 and ZAP 70 is dependent on its SH 2 domain , while c Cbl interacts with the carboxy terminal region . ^^^ These results suggest that the mechanism of action of SLAP 2 and the related protein SLAP is to promote c Cbl dependent degradation of the tyrosine kinases SYK and ZAP 70 and down regulation of CD 3 at the cell surface . . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| A mouse with a loss of function mutation in the c Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP 70 tyrosine kinase . ^^^ In marked contrast to the c Cbl knockout mouse , we found no evidence of enhanced activity of the ZAP 70 PTK in thymocytes from the TKB domain mutant mouse . ^^^ This finding contradicts the accepted mechanism of c Cbl mediated negative regulation , which requires TKB domain targeting of phosphotyrosine 292 in ZAP 70 . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| The complete elimination of PLC gamma 1 phosphorylation required deleting the SH 3 domain binding region of 70Z / 3 Cbl , consistent with 70Z / 3 Cbl binding the PLC gamma 1 SH 3 domain . 70Z / 3 Cbl induced PLC gamma 1 phosphorylation required Zap 70 , as for the TCR , and the tyrosine kinase binding domain of 70Z / 3 Cbl , which binds Zap 70 , but did not require PLC gamma 1 binding to Lat , a crucial interaction in TCR induced PLC gamma 1 phosphorylation . ^^^ Furthermore , 70Z / 3 Cbl induced activation of NFAT , a PLC gamma 1 / Ca ( 2+ ) dependent transcriptional event , required Zap 70 , but was independent of Slp 76 , an adapter required for TCR induced NFAT activation . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Taken together , these results suggest that rosmarinic acid has the potential to specifically inhibit Lck SH 2 domain binding to its cognate ligand , including ZAP 70 , Cbl , HS 1 , and PLCgamma 1 , and Lck dependent Ca 2+ signaling pathway of its downstream effector and finally to modulate IL 2 gene expression after T cell activation . . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| Crk proteins were found to be involved in the early steps of lymphocyte activation through their SH 2 mediated transient interaction with signal transducing molecules , such as Cbl , ZAP 70 , CasL , and STAT 5 . ^^^ |
|
| Interacting proteins: P43403 and P22681 |
Pubmed |
SVM Score :0.0 |
| We analyzed the effect of mutation of a cbl binding site on ZAP 70 ( ZAP Y292F ) on dynamics , internalization , and degradation of the TCR / CD3 complex in response to distinct stimuli . ^^^ This study identifies a step involving ZAP 70 / cbl interaction that is critical for rapid internalization of the TCR / CD3 complex at the CD 8 T cell / APC synapse . . ^^^ |
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