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H Band

Publications and source records attributed to H Band.

At least 19 recordsLinked to original sources
PubMed2001

The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquitylation upon B-cell receptor stimulation.

The negative regulator Cbl functions as a ubiquitin ligase towards activated receptor tyrosine kinases and facilitates their transport to lysosomes. Whether Cbl ubiquitin ligase activity mediates its negative regulatory effects on cytoplasmic tyrosine kinases of the Syk/ZAP-70 family has not been addressed, nor is it known whether these kinases are regulated via ubiquitylation during lymphocyte B-cell receptor engagement. Here we show that B-cell receptor stimulation in Ramos cells induces the ubiquitylation of Syk tyrosine kinase which is inhibited by a dominant-negative mutant of Cbl. Intact tyrosine kinase-binding and RING finger domains of Cbl were found to be essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. These same domains were also essential for Cbl-mediated negative regulation of Syk as measured using an NFAT-luciferase reporter in a lymphoid cell. Association with Cbl did not alter the kinase activity of Syk. Altogether, our results support an essential role for Cbl ubiquitin ligase activity in the negative regulation of Syk, and establish that ubiquitylation provides a mechanism of Cbl-mediated negative regulation of cytoplasmic targets.

Cell Line↗
PubMed2001

Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein.

The c-Cbl protooncogene is a negative regulator for several receptor tyrosine kinases (RTKs) through its ability to promote their polyubiquitination. Hence, uncoupling c-Cbl from RTKs may lead to their deregulation. In testing this, we show that c-Cbl promotes ubiquitination of the Met RTK. This requires the c-Cbl tyrosine kinase binding (TKB) domain and a juxtamembrane tyrosine residue on Met. This tyrosine provides a direct binding site for the c-Cbl TKB domain, and is absent in the rearranged oncogenic Tpr-Met variant. A Met receptor, where the juxtamembrane tyrosine is replaced by phenylalanine, is not ubiquitinated and has transforming activity in fibroblast and epithelial cells. We propose the uncoupling of c-Cbl from RTKs as a mechanism contributing to their oncogenic activation.

Animals↗
PubMed2000

The linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells.

The protooncogene product Cbl has emerged as a negative regulator of tyrosine kinases. We have shown previously that Cbl binds to ZAP-70 through its N-terminal tyrosine kinase binding (TKB) domain. In this study, we demonstrate that overexpression of Cbl in Jurkat T cells decreases the TCR-induced phosphorylation of ZAP-70 and other cellular phosphoproteins. Coexpression of Cbl with ZAP-70 in COS cells reproduced the Cbl-induced reduction in the level of phosphorylated ZAP-70. The effect of Cbl was eliminated by the TKB-inactivating G306E mutation in Cbl as well as by a phenylalanine mutation of Tyr292 within the TKB domain binding site on ZAP-70. Notably, the oncogenic Cbl-70Z/3 mutant associated with ZAP-70, but did not reduce the levels of phosphorylated ZAP-70. Overexpression of Cbl, but not Cbl-G306E, in Jurkat T cells led to a decrease in the TCR-induced NF-AT luciferase reporter activity. Overexpression of the TKB domain itself, but not its G306E mutant, functioned in a dominant-negative manner and led to an increase in NF-AT reporter activity. Cbl-70Z/3-overexpressing cells exhibited an increase in both basal and TCR-induced NF-AT luciferase reporter activity, and this trend was reversed by the G306E mutation. Finally, by reconstituting a ZAP-70-deficient Jurkat T cell line, p116, we demonstrate that wild-type ZAP-70 is susceptible to the negative regulatory effect of Cbl, whereas the ZAP-70-Y292F mutant is resistant. Together, our results establish that the linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells.

Animals↗
PubMed2000

Src family kinases negatively regulate platelet-derived growth factor alpha receptor-dependent signaling and disease progression.

We tested the hypothesis that Src family kinases (SFK) contribute to c-Cbl-mediated degradation of the platelet-derived growth factor (PDGF) alpha receptor (alphaPDGFR). Using either a receptor mutant that does not engage SFKs (F72/74), or cells that that lack SFKs, we found that SFKs contributed to degradation of the alphaPDGFR. Overexpression of c-Cbl also reduced the receptor half-life, but only if the receptor was able to engage SFKs. In cultured cells, prolonging the half-life of the receptor correlated with enhanced signaling and more efficient S phase entry, whereas accelerating receptor degradation had the opposite effect. Consistent with these tissue culture findings, there was a statistically significant increase in the onset of a proliferative retinal disease when animals were injected with cells expressing the F72/74 receptor, as compared with cells expressing the WT receptor. Our findings suggest that SFKs cooperate with c-Cbl to negatively regulate the alphaPDGFR, and that the SFK/c-Cbl suppression of alphaPDGFR output is relevant to the onset and progression of a proliferative disease.

3T3 Cells↗
PubMed2000

The evolutionarily conserved N-terminal region of Cbl is sufficient to enhance down-regulation of the epidermal growth factor receptor.

The mammalian proto-oncoprotein Cbl and its homologues in Caenorhabditis elegans and Drosophila are evolutionarily conserved negative regulators of the epidermal growth factor receptor (EGF-R). Overexpression of wild-type Cbl enhances down-regulation of activated EGF-R from the cell surface. We report that the Cbl tyrosine kinase-binding (TKB) domain is essential for this activity. Whereas wild-type Cbl enhanced ligand-dependent EGF-R ubiquitination, down-regulation from the cell surface, accumulation in intracellular vesicles, and degradation, a Cbl TKB domain-inactivated mutant (G306E) did not. Furthermore, the transforming truncation mutant Cbl-N (residues 1-357), comprising only the Cbl TKB domain, functioned as a dominant negative protein. It colocalized with EGF-R in intracellular vesicular structures, yet it suppressed down-regulation of EGF-R from the surface of cells expressing endogenous wild-type Cbl. Therefore, Cbl-mediated down-regulation of EGF-R requires the integrity of both the N-terminal TKB domain and additional C-terminal sequences. A Cbl truncation mutant comprising amino acids 1-440 functioned like wild-type Cbl in down-regulation assays. This mutant includes the evolutionarily conserved TKB and RING finger domains but lacks the less conserved C-terminal sequences. We conclude that the evolutionarily conserved N terminus of Cbl is sufficient to effect enhancement of EGF-R ubiquitination and down-regulation from the cell surface.

Amino Acid Sequence↗
PubMed2000

The RING finger domain of Cbl is essential for negative regulation of the Syk tyrosine kinase.

The proto-oncogene product Cbl has emerged as a negative regulator of a number of protein-tyrosine kinases, including the ZAP-70/Syk tyrosine kinases that are critical for signaling in hematopoietic cells. The evolutionarily conserved N-terminal tyrosine kinase-binding domain is required for Cbl to associate with ZAP-70/Syk and for their subsequent negative regulation. However, the role of the remaining C-terminal regions of Cbl remains unclear. Here, we used a COS-7 cell reconstitution system to address this question. Analysis of a series of C-terminally truncated Cbl mutants revealed that the N-terminal half of the protein, including the TKB and RING finger domains, was sufficient to mediate negative regulation of Syk. Further truncations, which delete the RING finger domain, abrogated the negative regulatory effects of Cbl on Syk. Point mutations of conserved cysteine residues or a histidine in the RING finger domain, which are required for zinc binding, abrogated the ability of Cbl to negatively regulate Syk in COS-7 cells and Ramos B lymphocytic cells. In addition, Syk-dependent transactivation of a serum response element-luciferase reporter in transfected 293T cells was reduced by wild type Cbl; mutations of the RING finger domain or its deletion abrogated this effect. These results establish the RING finger domain as an essential element in Cbl-mediated negative regulation of a tyrosine kinase and reveal that the evolutionarily conserved N-terminal half of the protein is sufficient for this function.

Amino Acid Sequence↗
PubMed2000

T cell receptor-dependent activation of human lymphocytes through cell surface ganglioside GT1b: implications for innate immunity.

Gangliosides form a component of the glycosphingolipid-rich membrane microdomains recently shown to play an important role in receptor signal transduction. Specific gangliosides also serve as receptors for binding and internalization of bacterial toxins. In the course of characterizing the basis of the native tetanus toxin (TTx) reactivity of a human gamma delta T cell clone, we observed that transfer of the TCR was required to impart TTx reactivity on a TCR-negative recipient T cell. However, the reconstitution of toxin reactivity could be achieved regardless of the antigen specificity of the TCR chains. Further analysis showed that the T cell recognition of native TTx was dependent on the presence of its ganglioside receptor, GT1b, on the T cell surface. Incorporation of exogenous GT1b into plasma membrane conferred TTx reactivity on otherwise non-reactive T cells provided these cells expressed the TCR. Finally, reconstitution of TCR-negative Jurkat T cells with a CD8-CD3zeta chain chimera demonstrated that the cytoplasmic region of the CD3zeta chain was sufficient to couple ganglioside-mediated TTx binding to T cell activation. These data reveal a novel mode of TCR-dependent reactivity to a bacterial toxin that could mobilize a large subset of T cells, thus representing a form of innate immunity. Given the possibility that endogenous ligands may bind to cell surface gangliosides, regulation of their levels and topology on the cell surface may constitute an immunoregulatory mechanism.

Cell Line, Transformed↗
PubMed2000

Cbl-transforming variants trigger a cascade of molecular alterations that lead to epithelial mesenchymal conversion.

Dispersal of epithelial cells is an important aspect of tumorigenesis, and invasion. Factors such as hepatocyte growth factor induce the breakdown of cell junctions and promote cell spreading and the dispersal of colonies of epithelial cells, providing a model system to investigate the biochemical signals that regulate these events. Multiple signaling proteins are phosphorylated in epithelial cells during hepatocyte growth factor-induced cell dispersal, including c-Cbl, a protooncogene docking protein with ubiquitin ligase activity. We have examined the role of c-Cbl and a transforming variant (70z-Cbl) in epithelial cell dispersal. We show that the expression of 70z-Cbl in Madin-Darby canine kidney epithelial cells resulted in the breakdown of cell-cell contacts and alterations in cell morphology characteristic of epithelial-mesenchymal transition. Structure-function studies revealed that the amino-terminal portion of c-Cbl, which corresponds to the Cbl phosphotyrosine-binding/Src homology domain 2, is sufficient to promote the morphological changes in cell shape. Moreover, a point mutation at Gly-306 abrogates the ability of the Cbl Src homology domain 2 to induce these morphological changes. Our results identify a role for Cbl in the regulation of epithelial-mesenchymal transition, including loss of adherens junctions, cell spreading, and the initiation of cell dispersal.

Animals↗
PubMed2000

The Cbl proto-oncogene product negatively regulates the Src-family tyrosine kinase Fyn by enhancing its degradation.

Fyn is a prototype Src-family tyrosine kinase that plays specific roles in neural development, keratinocyte differentiation, and lymphocyte activation, as well as roles redundant with other Src-family kinases. Similar to other Src-family kinases, efficient regulation of Fyn is achieved through intramolecular binding of its SH3 and SH2 domains to conserved regulatory regions. We have investigated the possibility that the tyrosine kinase regulatory protein Cbl provides a complementary mechanism of Fyn regulation. We show that Cbl overexpression in 293T embryonic kidney and Jurkat T-lymphocyte cells led to a dramatic reduction in the active pool of Fyn; this was seen as a reduction in Fyn autophosphorylation, reduced phosphorylation of in vivo substrates, and inhibition of transcription from a Src-family kinase response element linked to a luciferase reporter. Importantly, a Fyn mutant (FynY528F) relieved of intramolecular repression was still negatively regulated by Cbl. The Cbl-dependent negative regulation of Fyn did not appear to be mediated by inhibition of Fyn kinase activity but was correlated with enhanced protein turnover. Consistent with such a mechanism, elevated levels of Fyn protein were observed in cell lines derived from Cbl(-/-) mice compared to those in wild-type controls. The effects of Cbl on Fyn were not observed when the 70ZCbl mutant protein was analyzed. Taken together, these observations implicate Cbl as a component in the negative regulation of Fyn and potentially other Src-family kinases, especially following kinase activation. These results also suggest that protein degradation may be a general mechanism for Cbl-mediated negative regulation of activated tyrosine kinases.

Amino Acid Substitution↗
PubMed1999

Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation. A critical role for Cbl tyrosine kinase-binding domain.

The Cbl proto-oncogene product has emerged as a novel negative regulator of receptor and non-receptor tyrosine kinases. Our previous observations that Cbl overexpression in NIH3T3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) and that the expression of oncogenic Cbl mutants up-regulated the PDGFRalpha signaling machinery strongly suggested that Cbl negatively regulates PDGFRalpha signaling. Here, we show that, similar to PDGFRalpha, selective stimulation of PDGFRbeta induces Cbl phosphorylation, and its physical association with the receptor. Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha. We show that Cbl-dependent negative regulation of PDGFRalpha and beta results in a reduction of PDGF-induced cell proliferation and protection against apoptosis. A point mutation (G306E) that inactivates the tyrosine kinase binding domain in the N-terminal transforming region of Cbl compromised the PDGF-inducible tyrosine phosphorylation of Cbl although this mutant could still associate with the PDGFR. More importantly, the G306E mutation abrogated the ability of Cbl to enhance the ligand-induced ubiquitination and degradation of the PDGFR and to inhibit the PDGF-dependent cell proliferation and protection from apoptosis. These results demonstrate that Cbl can negatively regulate PDGFR-dependent biological responses and that this function requires the conserved tyrosine kinase binding domain of Cbl.

3T3 Cells↗
PubMed1999

Role of Syk in Fc gamma receptor-coupled tyrosine phosphorylation of Cbl in a manner susceptible to inhibition by protein kinase C.

Fcgamma receptors (FcgammaR) of guinea pig neutrophils were ligated and anti-Cbl immunoprecipitates prepared therefrom were assayed for the associated protein tyrosine kinase activity, which increased upon ligation of FcgammaR. The increases were overcome upon activation of cellular protein kinase C by simultaneous addition of phorbol 12-myristate 13-acetate (PMA) to the ligated cells. Syk proved to be the most important tyrosine kinase bound to Cbl that served as the major substrate; essentially no tyrosine phosphorylation occurred in the anti-Cbl immunoprecipitates prepared from the cell lysate that had been depleted of Syk by prior immunoprecipitation with anti-Syk antibodies. Exposure of the (32)P-labeled cells to PMA resulted in phosphorylation of cellular Cbl on serine residues. Thus, protein kinase C-induced serine phosphorylation of Cbl suppressed its tyrosine phosphorylation by Syk as a result of tyrosine kinase inhibition by unknown mechanisms, leading to inhibition of Cbl-mediated signaling such as phosphatidylinositol 3-kinase activation.

Animals↗
PubMed1998

Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323.

The proto-oncogene product Cbl has emerged as a potential negative regulator of the Syk tyrosine kinase; however, the nature of physical interactions between Cbl and Syk that are critical for this negative regulation remains unclear. Here we show that the phosphotyrosine-binding (PTB) domain within the N-terminal transforming region of Cbl (Cbl-N) binds to phosphorylated Tyr323 in the linker region between the Src homology 2 and kinase domains of Syk, confirming recent results by another laboratory using the yeast two-hybrid approach (Deckert, M., Elly, C., Altman, A., and Liu, Y. C. (1998) J. Biol. Chem. 273, 8867-8874). A PTB domain-inactivating point mutation (G306E), corresponding to a loss-of-function mutation in the Caenorhabditis elegans Cbl homologue SLI-1, severely compromised Cbl-N/Syk binding in vitro and Cbl/Syk association in transfected COS-7 cells. Using heterologous expression in COS-7 cells, we investigated the role of Cbl PTB domain binding to Syk Tyr323 in the negative regulation of Syk. Co-expression of Cbl with Syk in COS-7 cells led to a dose-dependent decrease in the autophosphorylated pool of Syk and in phosphorylation of an in vivo substrate, CD8-zeta. Unexpectedly, these effects were largely due to the loss of Syk protein. Both the decrease in Syk and CD8-zeta phosphorylation and reduction in Syk protein levels were blocked by either G306E mutation in Cbl or by Y323F mutation in Syk. These results demonstrate a critical role for the Cbl PTB domain in the recruitment of Cbl to Syk and in Cbl-mediated negative regulation of Syk.

Binding Sites↗
PubMed1998

Association of p59(fyn) with the T lymphocyte costimulatory receptor CD2. Binding of the Fyn Src homology (SH) 3 domain is regulated by the Fyn SH2 domain.

Human CD2 is a 50-55-kDa cell surface receptor specifically expressed on the surface of T lymphocytes and NK cells. Stimulation of human peripheral blood T cells with mitogenic pairs of anti-CD2 monoclonal antibodies (mAbs) is sufficient to induce interleukin-2 production and T cell proliferation in the absence of an antigen-specific signal through the T cell receptor. CD2 has been shown previously to associate physically with the Src family protein-tyrosine kinases p56(lck) and p59(fyn). We now report that stimulation of T cells with mitogenic pairs of anti-CD2 mAbs enhanced the association of the Fyn polypeptide with the CD2 complex, whereas stimulation with single anti-CD2 mAb had minimal effect. Using glutathione S-transferase (GST) fusion proteins, we found that CD2 bound to the Src homology (SH) 3 domain of Fyn. Interestingly, the CD2-Fyn association was negatively regulated by the Fyn SH2 domain; CD2 bound poorly to GST fusion proteins expressing both the SH2 and SH3 domains of Fyn. However, the inhibitory effect of the Fyn SH2 domain on binding of the Fyn SH3 domain to CD2 was relieved by peptides containing a phosphorylated YEEI sequence that bound directly to the Fyn SH2 domain. In addition, we found that the ability of the Fyn SH2 domain to precipitate tyrosine-phosphorylated proteins, including the CD3zeta chain, was enhanced after T cell stimulation with mitogenic pairs of CD2 mAbs. Finally, overexpression of a mutated Fyn molecule, in which the ability of the Fyn SH2 domain to bind phosphotyrosine-containing proteins was abrogated, inhibited CD2-induced transcriptional activation of the nuclear factor of activated T cells (NFAT), suggesting a functional involvement of the Fyn SH2 domain in CD2-induced T cell signaling. We thus propose that stimulation through the CD2 receptor leads to the tyrosine phosphorylation of intracellular proteins, including CD3zeta itself, which in turn bind to the Fyn-SH2 domain, allowing the direct association of the Fyn SH3 domain with CD2 and the initiation of downstream signaling events.

Antibodies↗
PubMed1998

The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor alpha.

The Cbl protooncogene product has emerged as a negative regulator of receptor and nonreceptor tyrosine kinases. We recently demonstrated that oncogenic Cbl mutants upregulate the endogenous tyrosine kinase signaling machinery when expressed in the NIH 3T3 cells, and identified the platelet-derived growth factor receptor-alpha (PDGFRalpha) as one of the tyrosine kinases targeted by these oncogenes. These findings suggested a role for the normal Cbl protein in negative regulation of the PDGFRalpha. However, the mechanism of such negative regulation remained to be determined. Here we show that overexpression of the wild-type Cbl enhances the ligand-induced ubiquitination of the PDGFRalpha. Concomitantly, the PDGFRalpha in Cbl-overexpressing cells undergoes a faster ligand-induced degradation compared with that in the control cells. These results identify a role for Cbl in the regulation of ligand-induced ubiquitination and degradation of receptor tyrosine kinases and suggest one potential mechanism for evolutionarily conserved negative regulatory influence of Cbl on tyrosine kinases.

3T3 Cells↗
PubMed1998

Crucial role of TCR gamma chain junctional region in prenyl pyrophosphate antigen recognition by gamma delta T cells.

Human gamma delta T cells recognize prenyl pyrophosphate Ags and their analogues in a V gamma 2V delta 2 TCR-dependent manner. Few data are available regarding the TCR structural requirements for recognition of such prenyl pyrophosphate Ags by gamma delta T cells. Presently, we made chain pair switch, chimeric, and site mutant gamma delta TCRs and transfected them into TCR- mutant Jurkat T cells to examine the effects of changing the TCR gamma junctional region sequences on reactivity to prenyl pyrophosphate Ags. Substitution of the TCR gamma junctional region (N and J) sequences from an Ag-reactive TCR with TCR gamma junctional region sequences from an Ag-nonreactive TCR abrogated reactivity to the prenyl pyrophosphate Ag isopentenyl pyrophosphate and to its synthetic analogue ethyl pyrophosphate but not to a mycobacterial supernatant containing a mixture of prenyl pyrophosphate Ags. Substitution of only the TCR gamma N nucleotide region with that from this Ag-nonreactive TCR destroyed reactivity to isopentenyl pyrophosphate and to the mycobacterial supernatant. Substitution of the entire V delta 2 chain from the Ag-reactive TCR with a V delta 1 chain from an Ag-nonreactive TCR yielded a prenyl pyrophosphate Ag-nonreactive TCR. Thus, using TCR mutagenesis and TCR transfectants, we show that gamma delta TCR reactivity to prenyl pyrophosphate Ags is dependent upon the junctional region of the TCR gamma chain and upon pairing of V gamma 2 and V delta 2 TCR chains. These structural requirements of TCR gamma delta recognition of prenyl pyrophosphates distinguish this reactivity from that of protein superantigens and emphasize the importance of the TCR gamma CDR3 loop and adjacent residues.

Amino Acid Sequence↗
PubMed1998

Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins.

Shb is a recently described Src homology 2 (SH2) domain-containing adaptor protein. Here we show that Shb is expressed in lymphoid tissues, and is recruited into signaling complexes upon activation of Jurkat T cells. Grb2 binds proline-rich motifs in Shb via its SH3 domains. As a result, a number of proteins detected in anti-Shb and anti-Grb2 immunoprecipitates are shared, including phosphoproteins of 22, 36/38, 55/57 and 70 kDa. Shb-association with p22, which represents the T cell receptor associated zeta chain, occurs through the Shb SH2 domain. The central region of Shb binds p36/38. Since this interaction was inhibited by phosphotyrosine, this region of Shb is likely to contain a non-SH2 PTB (phosphotyrosine binding) domain. The Shb PTB domain was found to preferentially bind the sequence Asp-Asp-X-pTyr when incubated with a phosphopeptide library. A peptide corresponding to a phosphorylation site in 34 kDa Lnk inhibited association between Shb and p36/38. Overexpression of Shb in Jurkat cells led to increased basal phosphorylation of Shb-associated p36/38 and p70 proteins. Inactivation of the Shb SH2 domain by an R522K mutation resulted in a reduced stimulation of tyrosine phosphorylation of several proteins in response to CD3 crosslinking when expressed in Jurkat cells. Together, our results show three distinct domains of Shb all participate in the formulation of multimeric signaling complexes in activated T cells. These results indicate that the Shb protein functions in T cell receptor signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The c-Cbl oncoprotein.

Cbl has emerged as a novel signal transducing protein downstream of a number of cell surface receptors coupled to tyrosine kinases. Identified as the protein product of the c-cbl proto-oncogene, the cellular homolog to the transforming gene of a murine retrovirus, Cbl comprises an N-terminal transforming region (Cbl-N), which contains a phosphotyrosine binding (PTB) domain, and a C-terminal modular region (Cbl-C) containing a RING finger motif, a large proline-rich region and a leucine zipper. Deletion of Cbl-C or small deletions N-terminal to the RING finger render Cbl oncogenic, whereas wild type Cbl is non-transforming, even if overexpressed. Cbl serves as a substrate of both receptor and non-receptor tyrosine kinases, and binds to adaptor proteins Grb2, Crk and the p85 subunit of PI-3-kinase. Additionally, both Caenorhabditis elegans and Drosophila Cbl homologs, SLI-1 and D-Cbl, respectively, have been identified as negative regulators of the LET-23/DER receptor tyrosine kinases. Finally, oncogenic mutants of Cbl, when expressed in fibroblasts, upregulate the signaling cascade downstream of the platelet-derived growth factor receptor alpha in a Cbl-PTB domain-dependent manner. Together, these findings position Cbl as a central player in the regulation of tyrosine kinase signaling pathways. Identification of the Cbl-PTB domain binding motifs on tyrosine kinases and elucidation of the mechanisms of Cbl's negative regulatory effect may provide a new avenue to control tyrosine kinases for therapeutic purposes.

Animals↗