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Cbl-B, a Member of the Sli-1/C-Cbl Protein Family, Inhibits Vav-Mediated C-Jun N-Terminal Kinase Activation

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Cbl-B, a Member of the Sli-1/C-Cbl Protein Family, Inhibits Vav-Mediated C-Jun N-Terminal Kinase Activation Oncogene (1997) 15, 2511 ± 2520 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated c-Jun N-terminal kinase activation Xose R Bustelo1,2, Piero Crespo3,4,MoÂnica Lo pez-Barahona1,5, J Silvio Gutkind3 and Mariano Barbacid1 1Department of Molecular Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543; 2Department of Pathology, School of Medicine and University Hospital, State University of New York at Stony Brook, Stony Brook, New York 11794; 3Laboratory of Cellular Development and Oncology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA We have used the yeast two-hybrid system to identify pleckstrin-homology (PH), cysteine-rich, SH3 and proteins that interact with Vav, a GDP/GTP exchange SH2 domains (for a review, see Bustelo 1996). The factor for the Rac-1 GTPase that plays an important important role of this gene during mitogenic and role in cell signaling and oncogenic transformation. This ontogenic processes was demonstrated by both cell experimental approach resulted in the isolation of Cbl-b, biology and genetic experiments. Thus, it has been a signal transduction molecule highly related to the shown that Vav can induce high levels of morpholo- mammalian c-cbl proto-oncogene product and to the C. gical transformation in rodent ®broblasts after deletion elegans Sli-1 protein, a negative regulator of the EGF- of N-terminal sequences (Katzav et al., 1989; Coppola receptor-like Let23 protein. The interaction between Vav et al., 1991). Moreover, disruption of the vav locus by and Cbl-b requires the entire SH3-SH2-SH3 carboxy- homologous recombination techniques results in severe terminal domain of Vav and a long stretch of proline-rich signaling defects of primary antigen receptors, leading sequences present in the central region of Cbl-b. to abnormal lymphocyte proliferation and lymphocy- Stimulation of quiescent rodent ®broblasts with either topenia (Fisher et al., 1995; Tarakhovski et al., 1995; epidermal or platelet-derived growth factors induces an Zhang et al., 1995). In T-cells this phenotype appears increased anity of Vav for Cbl-b and results in the to be mediated, at least in part, by insucient IL-2 subsequent formation of a Vav-dependent trimeric secretion after T-cell receptor cross-linking (Tara- complex with the ligand-stimulated tyrosine kinase khovski et al., 1995; Zhang et al., 1995). receptors. During this process, Vav, but not Cbl-b, At the biochemical level, Vav becomes tyrosine becomes highly phosphorylated on tyrosine residues. phosphorylated upon stimulation of hematopoietic Overexpression of Cbl-b inhibits the signal transduction receptors such as the T-cell receptor-CD4 complex pathway of Vav that leads to the stimulation of c-Jun N- (Bustelo et al., 1992; Margolis et al., 1992), the mast terminal kinase. By contrast, expression of truncated cell IgE high anity receptor (Margolis et al., 1992), Cbl-b proteins and of missense mutants analogous to the B-cell IgM antigen complex (Bustelo and Barbacid, those found in inactive Sli-1 proteins have no detectable 1992), the c-Kit and Flk-2 tyrosine kinase receptors eect on Vav activity. These results indicate that Vav (Alai et al., 1992; Dosil et al., 1993) and a large panel and Cbl-b act coordinately in the ®rst steps of tyrosine of cytokine receptors (Bustelo, 1996), further suggest- protein kinase receptor-mediated signaling and suggest ing that the function of Vav is required during the that members of the Sli-1/Cbl family are also negative earliest steps of receptor-mediated signal transduction. regulators of signal transduction in mammalian cells. Recent experimental evidence indicates that Vav acts as a guanosine-nucleotide exchange factor for the Keywords: Cbl family; Vav; tyrosine phosphorylation; GTP-binding protein Rac-1 (Crespo et al., 1997), a JNK activation GTPase of the Rho subfamily with roles in cytoskeletal architecture, cell proliferation, and cellular transforma- tion (for a review, see Ridley, 1995). This enzymatic activity is stimulated during cell signaling by the Introduction phosphorylation of Vav on tyrosine residues, leading to the transition of the Rac-1 GTPase from the inactive The vav gene was ®rst identi®ed by virtue of its (GDP-loaded) to the active (GTP-loaded state) (Crespo oncogenic activation during the course of gene transfer et al., 1997). Rac-1 activation leads in turn to the assays (Katzav et al., 1989). Its normal allele, the vav stimulation of intracellular routes such as the c-Jun N- proto-oncogene, encodes a 95 kDa polypeptide that terminal kinase (JNK) pathway (Crespo et al., 1996, harbors a complex array of structural domains, 1997). This biochemical activity appears to be mediated including leucine-rich, acidic, Dbl-homology (DH), by the Vav DH domain, since mutants of Vav with a non-functional DH motif do not induce Rac-1 nucleotide exchange nor JNK activation (Crespo et al., 1996, 1997). Correspondence: XR Bustelo and M Barbacid In addition to this catalytic role, other experimental Present addresses: 4Department of Molecular Biology, School of evidence suggests that protein-protein interactions also Medicine, Universidad de Cantabria, 39011 Santander, Spain 5Centro Universitario Francisco de Vitoria, Ctra, Pozuelo- take part in the regulation of Vav activity. In Majadahonda Km 1,800 28223 Pozuelo de Alarcon, Madrid, Spain. agreement with this notion, several reports have Received 6 May 1997; revised 15 July 1997; accepted 16 July 1997 indicated that the Vav SH2 and SH3 domains work Cbl-b is a negative regulator of Vav signaling XR Bustelo et al 2512 as autonomous heterodimerization motifs. As an domain (GBD) in a vector (pGBT) that directs low example, the Vav SH2 domain binds to ligand- levels of expression of the GBD fusion proteins stimulated mitogenic receptors such as the EGF and (Bustelo et al., 1995). As the tester strain, we used PDGF receptors (Bustelo et al., 1992; Margolis et al., YPB2 derivatives containing the bait plasmid and two 1992) as well as to cytoplasmic tyrosine-phosphory- Gal-4-inducible markers, HIS3andlacZ (Bartel et al., lated proteins such as the B-cell speci®c Vap-1 protein 1993). This tester strain was re-transformed with a (Bustelo and Barbacid, 1992), the T-cell speci®c Zap70 cDNA library derived from human B-lymphocytes protein tyrosine kinase (Katzav et al., 1994), members constructed in the pACT plasmid (Bartel et al., 1993), of the Jak and Btk families (Machide et al., 1995; a vector that directs the synthesis of fusion proteins Matsuguchi et al., 1995) and the hematopoietic-speci®c containing the Gal-4 transcriptional activation domain SLP-76 protein (Wu et al., 1996). These interactions (GAD). In those cases where a GAD fusion protein are likely to be mediated by the speci®c recognition of interacts with the bait protein, a functional Gal-4 the tyrosine phosphorylated YXEP (where X=M, L or activity is reconstituted leading to histidine proto- E) sequence motif by the Vav SH2 domain (Songyang trophy (HIS3) and b-galactosidase expression (lacZ) et al., 1994). On the other hand, the Vav SH3 domains (Bartel et al., 1993). have been identi®ed as targets for the association of a A total of 2.96106 transformants were placed in plethora of quite unrelated proteins such as Grb-2 (Ye selective media containing 15 mM 3-amino-1,2,4- and Baltimore, 1994), hnRNP-K (Hobert et al., 1994; triazole. Transformants showing histidine prototrophy Bustelo et al., 1995), the nuclear protein Ku-70 after one week of culture were subsequently screened (Romero et al., 1996) and the cytoskeletal protein for the ability to produce b-galactosidase using a ®lter zyxin (Hobert et al., 1996). These interactions are lift assay, resulting in a total of 30 positives. To test mediated by the recognition of speci®c proline-rich whether the phenotypes of those clones were dependent sequences by the Vav SH3 domains. Since these on the interaction with the GBD-Vav SH3-SH2-SH3 interactions do not require post-translational modifica- fusion protein, the plasmids of those colonies were tion of these proteins, they are likely to be constitutive selectively recovered in bacteria, grouped in three and independent of the mitogenic status of cells. At families by Southern blot hybridization, and represen- present, the biological signi®cance of these interactions tatives of each family re-introduced in YPB2 cells with remains to be determined. vectors encoding the Gal-4 DNA binding domain In this study, we have utilized the SH3-SH2-SH3 either alone or fused to the Vav SH3-SH2-SH3 domain of Vav as a probe to isolate novel Vav-binding region. As additional control, we performed parallel proteins by the two hybrid system (Bartel et al., 1993). experiments with a GBD fusion protein containing the This approach resulted in the identi®cation of two SH3-SH2-SH3 region of Vav-2, a Vav-related protein Vav-binding proteins, the already-described hnRNP-K with transforming potential that displays an ubiquitous (Hobert et al., 1994; Bustelo et al., 1995) and a second distribution (Schuebel et al., 1996). As illustrated in protein, designated Cbl-b (Keane et al., 1995), whose Figure 1a, the co-transformation of one of the library characterization is presented in this work. Cbl-b is a plasmids (pXRB85) with either the Vav or Vav-2 C- ubiquitously-expressed protein that binds to the terminal domains induced comparable levels of carboxy-terminal region of Vav through an interaction transcriptional activation of the lacZ gene. This mediated by a cluster of proline-rich sequences located transactivation was as strong as that observed with in the middle of the Cbl-b molecule. In addition, we the interaction between the yeast SNF4 and SNF1 show that overexpression of full length Cbl-b results in protein (Figure 1a).
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