Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase

  title={Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase},
  author={Wuyi Meng and Sansana Sawasdikosol and Steven J. Burakoff and Michael J. Eck},
Cbl is an adaptor protein that functions as a negative regulator of many signalling pathways that start from receptors at the cell surface. The evolutionarily conserved amino-terminal region of Cbl (Cbl-N) binds to phosphorylated tyrosine residues and has cell-transforming activity. Point mutations in Cbl that disrupt its recognition of phosphotyrosine also interfere with its negative regulatory function and, in the case of v-cbl, with its oncogenic potential. In T cells, Cbl-N binds to the… 

Structural basis for phosphorylation independent activation of c-CBL by Src-like adaptor protein 2

The results reveal that SLAP2 binding provides an alternative mechanism for activation of CBL ubiquitin ligase function, and disruption of the CBL/SLAP2 interface through mutagenesis demonstrates a role for this protein-protein interaction in regulation of C BL E3 ligase activity in cells.

The N Terminus of Cbl-c Regulates Ubiquitin Ligase Activity by Modulating Affinity for the Ubiquitin-conjugating Enzyme*

It is shown for the first time that phosphorylation of Tyr-341 or the Y341E mutation leads to a decrease in affinity for the ubiquitin-conjugating enzyme (E2), UbcH5b and that the decreased affinity of the Y 341E mutant Cbl-c for Ubch5b results in a more rapid turnover of bound Ubc H5b coincident with the increased E3 activity.

Structural Characterization of a Novel Cbl Phosphotyrosine Recognition Motif in the APS Family of Adapter Proteins*

A novel mode of phosphopeptide interaction is revealed with the Cbl T KB domain, in which N-terminal residues distal to the phosphotyrosine directly contact residues of the four-helix bundle of the TKB domain.

The RING Finger Domain of Cbl Is Essential for Negative Regulation of the Syk Tyrosine Kinase*

The RING finger domain is established as an essential element in Cbl-mediated negative regulation of a tyrosine kinase and revealed that the evolutionarily conserved N-terminal half of the protein is sufficient for this function.

A Conserved DpYR Motif in the Juxtamembrane Domain of the Met Receptor Family Forms an Atypical c-Cbl/Cbl-b Tyrosine Kinase Binding Domain Binding Site Required for Suppression of Oncogenic Activation*

By alanine-scanning mutagenesis, a DpYR motif including Tyr1003 is identified as being important for the direct recruitment of the c-Cbl TKB domain and for ubiquitination of the Met receptor.

Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin.

Additional Serine/Threonine Phosphorylation Reduces Binding Affinity but Preserves Interface Topography of Substrate Proteins to the c-Cbl TKB Domain

It is shown that additional phosphorylation significantly reduces the binding affinity between the TKB domain and its target proteins, EGFR and Sprouty2, as compared to peptides bearing a single tyrosine phosphorylated group.

The Evolutionarily Conserved N-terminal Region of Cbl Is Sufficient to Enhance Down-regulation of the Epidermal Growth Factor Receptor*

It is concluded that the evolutionarily conserved N terminus of Cbl is sufficient to effect enhancement of EGF-R ubiquitination and down-regulation from the cell surface.

SLAP2 adaptor binding disrupts c-CBL autoinhibition to activate ubiquitin ligase function

The results reveal that SLAP2 binding to a regulatory cleft of the TKBD provides an alternative mechanism for activation of CBL ubiquitin ligase function.



The Cbl Phosphotyrosine-binding Domain Selects a D(N/D)XpY Motif and Binds to the Tyr292Negative Regulatory Phosphorylation Site of ZAP-70*

A potential Cbl-PTB domain-dependent role for Cbl in the negative regulation of ZAP-70 is identified and potential PBTB domain binding sites on other protein tyrosine kinases known to interact with Cbl are predicted.

Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck

High-resolution crystallographic analysis of the Lck SH2 domain in complex with an 11-residue phosphopeptide derived from the hamster polyoma middle-T antigen, EPQpYEEIPIYL, shows the presence of a second pocket for the residue pY + 3 three positions C-terminal to the phosphotyrosine (pY).

Coordinated Regulation of the Tyrosine Phosphorylation of Cbl by Fyn and Syk Tyrosine Kinases*

Findings implicate Fyn as an adaptor protein that facilitates the interaction between Syk and Cbl, and suggest that Src and Syk family PTKs coordinately regulate the tyrosine phosphorylation of Cbl.

EGF receptor binding and transformation by v-cbl is ablated by the introduction of a loss-of-function mutation from the Caenorhabditis elegans sli-1 gene

V-cbl possesses a novel and evolutionarily conserved phosphotyrosine binding domain and that the dual capability of EGF receptor binding by cbl involves two distinct mechanisms, which raises the possibility that v-c Bl may transform by competing with c- cbl for phosphorylated binding sites on activated receptor complexes.

Interactions of Drosophila Cbl with epidermal growth factor receptors and role of Cbl in R7 photoreceptor cell development

D-Cbl functions as a negative regulator of receptor tyrosine kinase signaling in the Drosophila eye by a mechanism that involves its association with EGF receptors or other tyrosin kinases.

Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor

The crystal structure of the tandem SH2 domains of human ZAP-70 in complex with a peptide derived from the ζ-subunit of the T-cell receptor reveals an unanticipated interaction between the two domains that constitutes one of the two critical phosphotyrosine binding sites.

The Cbl protooncogene product: from an enigmatic oncogene to center stage of signal transduction.

Recent advances have firmly placed the little known protooncoprotein Cbl on the center stage of tyrosine kinase-mediated signal transduction.

c‐Cbl: A regulator of T cell receptor‐mediated signalling

The present review highlights some of the recent developments in understanding of Cbl function, with particular reference to its participation and possible roles in TCR‐mediated signalling.