Cbl
p210BCR/ABL induces formation of a multimeric complex of proteins that include p120c-Cbl,phosphotidylinositol-3' kinase, and p210BCR/ABL itself. Certain focal adhesion proteins are also part of this complex, including paxillin and talin. The sites in paxillin required to bind top120c-Cbl in this complex have been partially mapped. The interaction of pl20c-Cbl with paxillin is specific, since other focal adhesion proteins, such as p125FAK, vinculin, and alpha-actinin, are not in this complex. The binding of p120c-Cbl to the focal adhesion protein paxillin could contribute to the known adhesive defects of CML cells (Salgia, 1996).
Cbl is a Fyn/Lck SH3 and SH2 domain-binding protein that is tyrosine phosphorylated rapidly after T cell receptor triggering. This study demonstrates in vivo complexes of p120cbl with Fyn tyrosine kinase, the adaptor protein Grb2, and the p85 subunit of phosphatidylinositol (PI) 3-kinase. The association of p120cbl with Fyn and the p85 subunit of PI 3-kinase (together with PI 3-kinase activity)is markedly increased by T cell activation, consistent with in vitro binding of p120cbl to their SH2 as well as SH3 domains. In contrast, a large fraction of p120cbl was associated with Grb2 prior to activation, and this association does not change upon T cell activation. In vitro, p120cbl interacts withGrb2 exclusively through its SH3 domains. These results demonstrate a novel Grb2-p120cbl signaling complex in T cells, distinct from the previously analyzed Grb2-Sos complex. The association of p120cblwith ubiquitous signaling proteins strongly suggests a general signal transducing function for this enigmatic protooncogene with established leukemogenic potential but unknown physiological function (Fukazawa, 1995).
Stimulation of the T cell antigen receptor (TCR)/CD3 complex induces rapid tyrosine phosphorylation of Cbl, a proto-oncogene product that has been implicated in intracellular signaling pathways via its interaction with several signaling molecules. Cbl associates directly with a member of the 14-3-3 protein family (14-3-3tau) in T cells. The association is increased as a consequence of anti-CD3-mediated T cell activation. Phorbol stimulation of T cells also enhances the interaction between Cbl and two14-3-3 isoforms (tau and zeta). Tyrosine phosphorylation of Cbl is not sufficient or required for thisincreased interaction. Thus, cotransfection of COS cells with Cbl plus Lck and/or Syk family protein-tyrosine kinases causes a marked increase in the phosphotyrosine content of Cbl without a concomitant enhancement of its association with 14-3-3. Phorbol stimulation induces serine phosphorylation of Cbl, and dephosphorylation of immunoprecipitated Cbl by a Ser/Thr phosphatase disrupts its interaction with 14-3-3. The 14-3-3-binding domain maps to a serine-rich 30-amino acid region (residues615-644) of Cbl. Mutation of serine residues in this region further define a binding motif distinct from the consensus sequence RSXSXP, a 14-3-3-binding motif. The seresults suggest that TCR stimulation induces both tyrosine and serine phosphorylation of Cbl. These phosphorylation events allow Cbl to recruit distinct signaling elements that participate in TCR-mediated signal transduction pathways (Liu, 1997).
The protooncogenic protein c-Cbl is known to regulate the actin cytoskeleton. c-Cbl can also regulate the microtubular network. c-Cbl binds to tubulin and microtubules through its tyrosine kinase binding (TKB) domain. However, the character of the interactions described in this report is novel, since the G306E mutation, which disrupts the ability of c-Cbl's TKB to bind to tyrosine-phosphorylated proteins, does not affect the observed interaction between c-Cbl and microtubules. Furthermore, overexpression of c-Cbl in human pulmonary artery endothelial cells and COS-7 cells leads to microtubule stabilization. This effect of c-Cbl is mediated by TKB, and, like c-Cbl binding to microtubules, is independent of the ability of TKB to bind to tyrosine-phosphorylated proteins. Finally, c-Cbl has been shown to directly polymerize microtubules in vitro, and TKB is necessary and sufficient for this effect of c-Cbl. In this last phenomenon, as well as in the previous ones, the effect of TKB is not sensitive to the inactivating G306E mutation. Overall, the results suggest a novel function for c-Cbl-microtubule binding and stabilization (Teckchandani, 2005).
SH3 domains are protein modules that interact with proline-rich polypeptide fragments. Cbl is an
adapter-like protein known to interact with several SH3 domains, including the PLCgamma1 SH3
domain and the Grb2 amino terminal SH3 domain. Do sequences surrounding
the PLCgamma1 SH3 domain core sequence (aa.796-851) affect the binding to Cbl, a target used
as a prototypical ligand? A weak binding of
Cbl to GST fusion proteins that strictly encompass the structural core of the PLCgamma1 SH3 domain has been demonstrated
but a high-avidity binding occurs to the Grb2 amino-terminal SH3 domain. Inclusion of amino acids
immediately flanking the PLCgamma1 SH3 core domain, however, substantially increase binding of
Cbl to a level comparable to that of the Grb2 amino-terminal SH3 domain. The interaction of this
extended PLCgamma1 SH3 domain fusion protein with Cbl depends entirely on the
interaction of the domain with a proline-rich motif in Cbl, ruling out the possibility that amino acids
adjacent to the core SH3 domain of PLCgamma1 provide independent Cbl binding. These data suggest
that sequences surrounding the SH3 domain of PLCgamma1 may contribute to or stabilize the
association of the domain with the target protein, thus increasing its binding efficiency (Graham, 1998).
The protein product of the c-Cbl proto-oncogene is prominently tyrosine phosphorylated in response toi nsulin in 3T3-L1 adipocytes but not in 3T3-L1 fibroblasts. After insulin-dependent tyrosine phosphorylation, c-Cbl specifically associates with endogenous c-Crk and Fyn. These results suggest a role for tyrosine-phosphorylated c-Cbl in 3T3-L1 adipocyte activation by insulin. A yeast two-hybrid cDNA library prepared from fully differentiated 3T3-L1 adipocytes was screened with full-length c-Cbl as the target protein in an attempt to identify adipose-specific signaling proteins that interact with c-Cbl and potentially are involved in its tyrosine phosphorylation in 3T3-L1 adipocytes. A novel protein that has been termed CAP for c-Cbl-associated protein was isolated. CAP contains a unique structure with three adjacent Src homology 3 (SH3) domains in the C terminus and a region showing significant sequence similarity with the peptide hormone sorbin. Both CAP mRNA and proteins are expressed predominately in 3T3-L1 adipocytes but not in 3T3-L1 fibroblasts. CAP associates with c-Cbl in 3T3-L1 adipocytes independent of insulin stimulation in vivo; in vitro, CAP associates in an SH3-domain-mediated manner. CAP associates with the insulin receptor: insulin stimulation results in the dissociation of CAP from the insulin receptor. Taken together, these data suggest that CAP represents a novel c-Cbl binding protein in 3T3-L1 adipocytes likely to participate in insulin signaling (Ribon, 1998).
Interferon regulatory factor (IRF)-8/interferon consensus sequence-binding protein is regulated by both transcription and degradation. IRF-8 induced in peritoneal macrophages by interferon-gamma and lipopolysaccharide is degraded rapidly, and degradation of IRF-8 is blocked by MG132, the proteasome inhibitor, but inhibitors of calpain and lysosomal enzymes have no effect. The ubiquitination of IRF-8 was shown by co-immunoprecipitation from RAW264.7 macrophages retrovirally transduced with IRF-8 and hemagglutinin-ubiquitin. The dominant negative ubiquitin mutants K48R and K29R inhibit IRF-8 degradation in 293T cells, confirming the relationship between ubiquitination of IRF-8 and its degradation. IRF-8 carboxyl-terminal truncation mutants are not ubiquitinated and are consequently stable, indicating that the carboxyl-terminal domain of IRF-8 controls ubiquitination. The ubiquitin-protein isopeptide ligase (E3) that ubiquitinated IRF-8 is likely to be Cbl, which forms a complex with IRF-8, demonstrable by both immunoprecipitation and gel filtration. Furthermore, IRF-8 stability is increased by dominant negative Cbl, and IRF-8 ubiquitination is significantly attenuated in Cbl-/- cells. Reflecting increased stability and expression, the IRF-8 carboxyl-terminal deletion mutant induces interleukin (IL)-12 p40 promoter activity much more strongly than does IRF-8. Furthermore, IRF-8-induced IL-12 p40 synthesis in RAW264.7 cells is enhanced by dominant negative Cbl, and peritoneal macrophages from Cbl-/- mice show increased IL-12 p40 protein production. Taken together, these results suggest that the proteasomal degradation of IRF-8 mediated by the ubiquitin E3 ligase Cbl down-regulates IL-12 expression (Xiong, 2005).
During development of the skeleton, osteoclast (OC) recruitment and migration are required for the vascular invasion of the cartilaginous anlage and the ossification of long bones. c-Cbl lies downstream of the vitronectin receptor and forms a complex with c-Src and Pyk2 in a signaling pathway that is required for normal osteoclast motility. To determine whether the decreased motility observed in vitro in c-Cbl-/- OCs translates into decreased cell migration in vivo, the long bones of c-Cbl-/- mice were analyzed during development. Initiation of vascularization and replacement of cartilage by bone are delayed in c-Cbl-/- mice, due to decreased osteoclast invasion of the hypertrophic cartilage through the bone collar. Furthermore, c-Cbl-/- mice show a delay in the formation of secondary centers of ossification, a thicker hypertrophic zone of the growth plate, and a prolonged presence of cartilaginous remnants in the spongiosa, confirming a decrease in resorption of the calcified cartilage. Thus, the decrease in motility of c-Cbl-/- osteoclasts observed in vitro results in a decreased ability of osteoclasts to invade and resorb bone and mineralized cartilage in vivo. These results confirm that c-Cbl plays an important role in osteoclast motility and resorbing activity (Chiusaroli, 2003).
Transforming growth factor-beta is thought to regulate ductal and lobuloalveolar development as well as involution in the mammary gland. In an attempt to understand the role TGF-beta plays during normal mammary gland development, and ultimately cancer, transgenic mice were generated that express a dominant-negative TGF-beta type II receptor under control of the metallothionine promoter (MT-DNIIR). Upon stimulation with zinc sulfate, the transgene is expressed in the mammary stroma and results in an increase in ductal side branching. Mammary gland transplantation experiments confirm that the increase in side branching observed is due to DNIIR activity in the stroma. Development during puberty through the end buds is also accelerated. Cbl is a multifunctional intracellular adaptor protein that regulates receptor tyrosine kinase ubiquitination and downregulation. Mice with a targeted disruption of the c-Cbl gene display increased side branching similar to that observed in MT-DNIIR mice; however, end bud development during puberty is normal. Transplantation experiments show that the mammary stroma is responsible for the increased side branching observed in Cbl-null mice. Cbl expression is reduced in mammary glands from DNIIR mice compared to controls and TGF-beta stimulates expression of Cbl in cultures of primary mammary fibroblasts. In addition, both TGF-beta and Cbl regulate platelet-derived growth factor receptor-alpha (PDGFR alpha) expression in vivo and in isolated mammary fibroblasts. The hypothesis that TGF-beta mediates the levels of PDGFR alpha protein via regulation of c-Cbl was tested. It is concluded that TGF-beta regulates PDGFR alpha in the mammary stroma via a c-Cbl-independent mechanism. Finally, the effects of PDGF-AA on branching were determined. Treatment in vivo with PDGF-AA does not affect branching, making a functional interaction between TGF-beta and PDGF unlikely (Crowley, 2005).
CBL and CBL-B ubiquitin ligases (see Drosophila Cbl) are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. This study used the MMTV-Cre-mediated Cbl gene deletion on a Cbl-b-null background as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl/Cbl-b double knockout (DKO), using Lgr5-GFP-CreERT, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifen (TAM)-inducible Cbl/Cbl-b deletion model with a dual fluorescent reporter (Cblflox/flox; Cbl-bflox/flox; Rosa26-CreERT; mT/mG), it was shown that Cbl/Cbl-b DKO in mammary organoids leads to hyper-activation of AKT-mTOR signaling with depletion of MaSCs. Chemical inhibition of AKT or mTOR rescued MaSCs from Cbl/Cbl-b DKO induced depletion. These studies reveal a novel, cell-autonomous, requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling (Mohapatra, 2017).
The product of the vav proto-oncogene is expressedexclusively in hematopoietic cells and has guanine nucleotide exchange activity. Granulocyte/macrophage-colony- stimulating factor (GM-CSF), interleukin-3, and erythropoietin (Epo) induce rapid and transient tyrosine phosphorylation of Vav and Vav is constitutively associatedwith the SH3 domain of Grb2/Ash in a human leukemia cell line UT-7. These data implicate Vav in asignaling pathway leading to activation of Ras (See Drosophila Ras) or Ras-related proteins in hematopoietic cells. The proto-oncogene c-cbl product is also tyrosine-phosphorylated by stimulation with GM-CSF or Epo and is constitutively associated with theSH3 domain of Grb2/Ash in UT-7 (Hanazono, 1996).
B-cell antigen receptor (BCR) stimulation induces tyrosine phosphorylation of the Shc adaptor protein and its association with Grb2. The Shc/Grb2 complex may be involved in Ras activation, since Grb2interacts with the guanine nucleotide exchange factor Sos. There is an additional complexity ofthe BCR-induced Shc/Grb2 complex: it contains tyrosine phosphorylated proteins of 130, 110 and 75kDa. The 130 kDa molecule inducibly associates with Shc, while the 75 kDa protein interacts with the carboxy-terminal SH3 domain of Grb2. The 110 kDa molecule is defined as Cbl, the product of thec-cbl oncogene, which is strongly phosphorylated on tyrosine upon BCR stimulation. Cbl constitutively interacts with the SH3 domains of Grb2, with a preference for the amino-terminal domain, and is in thisway recruited to Shc upon BCR stimulation. Immunodepletion studies show that Grb2-associated Cbl can be phosphorylated by BCR-induced tyrosine kinases independent of a Shc/Grb2 interaction. This indicates that the BCR can also couple to a Grb2 complex without the involvement of Shc. Cbl not only interacts with Grb2, but also with the adaptor protein Crk. In contrast to its constitutive interaction withGrb2, tyrosine-phosphorylated Cbl only associates with Crk after BCR stimulation. In summary, the BCR activates Shc/Grb2-, Grb2- and Crk adaptor complexes of distinct composition, which may allow selective coupling to different signal transduction cascades. Cbl participates in all three adaptor complexes and is tyrosine phosphorylated upon BCR stimulation, pointing to a central role for this molecule in the regulation of antigen receptor-induced B cell responses (Smit, 1996).
The signaling pathways that arrest the cell cycle and trigger cell death are only partially known. Dimerization of CD38, a 45-kD transmembrane type II glycoprotein highly expressed in immature Bcells, inhibits cell growth and causes apoptosis in normal and leukemic B-cell progenitors, but the molecular mechanisms underlying these cellular responses are unknown. In the present study, it is found that CD38 ligation in the immature B-cell lines causes rapid tyrosine phosphorylation of the protein product of the proto-oncogene c-cbl. Dimerization of CD38 isaccompanied by the association of Cbl with the p85 subunit of phosphatidylinositol 3-kinase (Pl 3-K),resulting in markedly increased Pl 3-K activity in antiphosphotyrosine and anti-Cbl immunoprecipitates. Inhibitors of Pl 3-K rescue immature B cells fromCD38-mediated growth suppression. This effect is observed not only in model B-cell lines, but alsoin cultures of leukemic lymphoblasts from patients, and in normal bone marrow B-cell progenitors as well. These results suggest that Pl 3-K activity is essential for CD38-mediatedinhibition of lymphopoiesis and that Cbl and Pl 3-K are regulatory molecules whose activation can result in suppression of cell proliferation and apoptosis in immature lymphoid cells (Kitanaka, 1996).
Cbl is subject to early tyrosine phosphorylation upon stimulation of human B cell lines through surface IgM. Cbl also associates in vivo with Fyn and, to a lesser extent, other Src family kinases. B cell activation also induces a prominent association of Cbl with Syk tyrosine kinase. A substantial fraction of Cbl is constitutively associated with Grb2 and this interaction is mediated by Grb2 SH3 domains. Tyrosine-phosphorylated Shc, which prominently associates with Grb2, is detected in association with Cbl in activated B cells. Thus, Grb2 and Shc adaptors, which associate with immunoreceptor tyrosine based activation motifs, may link Cbl to the B cell receptor. B cell activation also induces an association between Cbl and the p85 subunit of phosphatidylinositol (PI) 3-kinase resulting in the association of a substantial fraction of PI 3-kinase activity with Cbl. Thus, Cbl is likely to play an important role in coupling the B cell receptor to the PI 3-kinase pathway. These results suggest arole for p120cbl in signaling downstream of the B cell receptor and support the idea that Cbl participates in a general signal transduction function downstream of the immune cell surface receptors (Panchamoorthy, 1996).
Crk, an adaptor protein, has been shown to bind to a tyrosine-phosphorylated protein of 116 kDa after TCR-mediated T cell activation. The Crk-associated p116 phosphoprotein is not the Crk-associated substrate(Cas) but, rather, is a protein product of the c-cbl proto-oncogene. Cbl becomes highly phosphorylated upon T cell activation. Crk immunoprecipitates from activated T cell lysates contain tyrosine-phosphorylated Cbl. This association is mediated by the SH2 domain of Crk. The Crk SH2 domain binds to a tyrosine-phosphorylated peptide corresponding to amino acids 770-781 of Cbl with high affinity. Cbl is a protein tyrosine kinase (PTK) substrate that becomes phosphorylated after engagement of numerous cell surface receptors including the TCR. The activation-dependent association between Crk and Cbl may represent another TCR-generated signal leading to Ras-related pathways (Sawasdikosol, 1996).
Cbl associates with all three forms of the human Crk protein, predominantly CrkL, following T cell receptor activation of Jurkat T cells. Association between Cbl and Crk proteins was confirmed in normal human peripheral blood-derived T cells. In vitro, Cbl is able to interact with the Crk SH2domain but not the SH3 domain. A phosphopeptide corresponding to a potential Crk SH2 domain-binding motif in Cbl (pYDVP) specifically inhibits binding between Cbl and Crk SH2 domain. Anti-Cbl antibody completely immunodepletes the CrkL-associated 120kDa phosphotyrosyl polypeptide, suggesting that the recently described p130cas-related Crk-associated p116 of T cells maybe Cbl. Consistent with this possibility, the 4F4 antibody used to characterize the p116 polypeptide cross-reacts with Cbl protein when it is resolved on one- or two-dimensional gels. CrkL is constitutively associated with a substantial amount of the guanine nucleotide exchange protein C3G,and a fraction of the C3G protein is coimmunoprecipitated with Cbl in activated Jurkat T cells. These results suggest the possibility that Cbl may participate in a signaling pathway that regulates guanine nucleotide exchange on small G-proteins in T cells (Reedquist, 1996).
The tyrosine protein kinase Zap-70 plays an essential role in T cellreceptor-mediated signal transduction. However, the model of action, as well as the physiologically relevant substrates of Zap-70, have not been determined. A 120-kDtyrosine-phosphorylated protein (p120) that associates with Zap-70 in activated T lymphocytes. The results of these analyses showed that p120 is encoded by the c-cbl protooncogene. The association of Zap-70 with c-Cbl is induced by T cell receptor stimulation, implying that it required posttranslational modification of one or both of these products. FynT, but not Lck, also associates with c-Cbl in activated T cells. Finally, using a heterologous system, it was demonstrated that the ability of Zap-70 to cause tyrosine phosphorylation of p120c-Cbl is dependent on Lck- or FynT-mediated signals. As c-Cbl can associate with several other signaling molecules, it may coupleZap-70 to downstream effectors during T cell activation (Fournel, 1996).
Engagement of the T-cell receptor (TCR)-CD3 complex induces a rapid increase in the activities of Src-family and
Syk/Zap-70-family kinases. These activated kinases then induce the tyrosine phosphorylation of multiple
intracellular proteins, eventually leading to T-cell activation. One of the prominent substrates for these kinases is the
adaptor protein Cbl. Recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70. Cbl-b, a homolog of Cbl, is widely expressed in many tissues and cells including hematopoietic cells.
Cbl-b undergoes rapid tyrosine phosphorylation upon stimulation of the TCR and cytokine receptors. However, the role of
Cbl-b is unclear. Overexpression of Cbl-b in T cells induces the constitutive activation of the
transcription factor nuclear factor of activated T cells (NFAT). A loss-of-function mutation in Cbl-b disrupts the
interaction between Cbl-b and Zap-70 and nearly completely abrogates the Cbl-b-mediated activation of NFAT. Unlike the
proposed role of Cbl as a negative regulator, these results suggest that the Cbl homolog Cbl-b has a positive role in T-cell
signaling, most likely via a direct interaction with the upstream kinase Zap-70 (Zhang, 1999).
Cbl is an adaptor protein that functions as a negative regulator of many signaling 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
tyrosine-phosphorylated inhibitory site of the protein tyrosine kinase ZAP-70. Described here is the crystal structure of Cbl-N, both alone and in complex with a
phosphopeptide that represents its binding site in ZAP-70. The structures show that Cbl-N is composed of three interacting domains: a four-helix bundle (4H), an
EF-hand calcium-binding domain, and a divergent SH2 domain that is not recognizable from the amino-acid sequence of the protein. The calcium-bound EF hand
wedges between the 4H and SH2 domains and roughly determines their relative orientation. In the ligand-occupied structure, the 4H domain packs against the SH2
domain and completes its phosphotyrosine-recognition pocket. Disruption of this binding to ZAP-70 as a result of structure-based mutations in the 4H, EF-hand and
SH2 domains confirms that the three domains together form an integrated phosphoprotein-recognition module (Meng, 1999).
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. This study shows 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 are essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. These same domains are also essential for Cbl-mediated negative regulation of Syk, as measured using an NFAT-luciferase reporter in a lymphoid cell. Association with Cbl does not alter the kinase activity of Syk. Altogether, these 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 (Rao, 2001).
T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. Using microarray analysis early growth response gene 2 (Egr-2) and Egr-3 have been identified as key negative regulators of T cell activation. Overexpression of Egr2 and Egr3 is associated with an increase in the E3 ubiquitin ligase Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr3-/- mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance. These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program (Safford, 2005).
The Cbl protooncogene product has emerged as a negative regulator of receptor and nonreceptor tyrosine kinases. Oncogenic Cbl mutants upregulate the endogenous tyrosine kinase signaling machinery when expressed in the NIH 3T3 cells, and the platelet-derived growth factor receptor-alpha (PDGFRalpha) has been identified 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 remains to be determined. 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 the evolutionarily conserved negative regulatory influence of Cbl on tyrosine kinases (Miyake, 1998).
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