This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bonita, D. P.
Right arrow Articles by Band, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bonita, D. P.
Right arrow Articles by Band, H.

 Previous Article  |  Next Article 

Mol. Cell. Biol., Aug 1997, 4597-4610, Vol 17, No. 8
Copyright © 1997, American Society for Microbiology

Phosphotyrosine binding domain-dependent upregulation of the platelet- derived growth factor receptor alpha signaling cascade by transforming mutants of Cbl: implications for Cbl's function and oncogenicity

DP Bonita, S Miyake, ML Lupher Jr, WY Langdon and H Band
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Recent studies have demonstrated that Cbl, the 120-kDa protein product of the c-cbl proto-oncogene, serves as a substrate of a number of receptor-coupled tyrosine kinases and forms complexes with SH3 and SH2 domain-containing proteins, pointing to its role in signal transduction. 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. Here, we show that expression of Cbl-N and two other transforming Cbl mutants (CblY368 delta and Cbl366-382 delta or Cb170Z), but not wild-type Cbl, in NIH 3T3 fibroblasts leads to enhancement of endogenous tyrosine kinase signaling. We identified platelet-derived growth factor receptor alpha (PDGFR alpha) as one target of mutant Cbl-induced deregulation. In mutant Cbl transfectants, PDGFR alpha was hyperphosphorylated and constitutively complexed with a number of SH2 domain-containing proteins. PDGFR alpha hyperphosphorylation and enhanced proliferation of mutant Cbl-transfected NIH 3T3 cells were drastically reduced upon serum starvation, and PDGF-AA substituted for the maintenance of these traits. PDGF-AA stimulation of serum-starved Cbl transfectants induced the in vivo association of transfected Cbl proteins with PDGFR alpha. In vitro, Cbl-N directly bound to PDGFR alpha derived from PDGF-AA- stimulated cells but not to that from unstimulated cells, and this binding was abrogated by a point mutation (G306E) corresponding to a loss-of-function mutation in SLI-1. The Cbl-N/G306E mutant protein, which failed to induce enhanced growth and transformation of NIH 3T3 cells, also failed to induce hyperphosphorylation of PDGFR alpha. Altogether, these findings identify a novel mechanism of Cbl's physiological function and oncogenesis, involving its PTB domain- dependent direct interaction with cellular tyrosine kinases.


This article has been cited by other articles:

  • Bandi, S. R., Brandts, C., Rensinghoff, M., Grundler, R., Tickenbrock, L., Kohler, G., Duyster, J., Berdel, W. E., Muller-Tidow, C., Serve, H., on behalf of the Study Alliance Leukemias, , Sargin, B. (2009). E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease. Blood 114: 4197-4208 [Abstract] [Full Text]  
  • Toffalini, F., Kallin, A., Vandenberghe, P., Pierre, P., Michaux, L., Cools, J., Demoulin, J.-B. (2009). The fusion proteins TEL-PDGFR{beta} and FIP1L1-PDGFR{alpha} escape ubiquitination and degradation. haematol 94: 1085-1093 [Abstract] [Full Text]  
  • Dunbar, A. J., Gondek, L. P., O'Keefe, C. L., Makishima, H., Rataul, M. S., Szpurka, H., Sekeres, M. A., Wang, X. F., McDevitt, M. A., Maciejewski, J. P. (2008). 250K Single Nucleotide Polymorphism Array Karyotyping Identifies Acquired Uniparental Disomy and Homozygous Mutations, Including Novel Missense Substitutions of c-Cbl, in Myeloid Malignancies. Cancer Res. 68: 10349-10357 [Abstract] [Full Text]  
  • Shen, M., Yen, A. (2008). c-Cbl Interacts with CD38 and Promotes Retinoic Acid-Induced Differentiation and G0 Arrest of Human Myeloblastic Leukemia Cells. Cancer Res. 68: 8761-8769 [Abstract] [Full Text]  
  • Langenick, J., Araki, T., Yamada, Y., Williams, J. G. (2008). A Dictyostelium homologue of the metazoan Cbl proteins regulates STAT signalling. J. Cell Sci. 121: 3524-3530 [Abstract] [Full Text]  
  • Reddi, A. L., Ying, G., Duan, L., Chen, G., Dimri, M., Douillard, P., Druker, B. J., Naramura, M., Band, V., Band, H. (2007). Binding of Cbl to a Phospholipase C{gamma}1-docking Site on Platelet-derived Growth Factor Receptor beta Provides a Dual Mechanism of Negative Regulation. J. Biol. Chem. 282: 29336-29347 [Abstract] [Full Text]  
  • Sargin, B., Choudhary, C., Crosetto, N., Schmidt, M. H. H., Grundler, R., Rensinghoff, M., Thiessen, C., Tickenbrock, L., Schwable, J., Brandts, C., August, B., Koschmieder, S., Bandi, S. R., Duyster, J., Berdel, W. E., Muller-Tidow, C., Dikic, I., Serve, H. (2007). Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110: 1004-1012 [Abstract] [Full Text]  
  • Miranda, M., Sorkin, A. (2007). Regulation of Receptors and Transporters by Ubiquitination: New Insights into Surprisingly Similar Mechanisms. Mol. Interv. 7: 157-167 [Abstract] [Full Text]  
  • Kaabeche, K., Lemonnier, J., Le Mee, S., Caverzasio, J., Marie, P. J. (2004). Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation. J. Biol. Chem. 279: 36259-36267 [Abstract] [Full Text]  
  • Duan, L., Miura, Y., Dimri, M., Majumder, B., Dodge, I. L., Reddi, A. L., Ghosh, A., Fernandes, N., Zhou, P., Mullane-Robinson, K., Rao, N., Donoghue, S., Rogers, R. A., Bowtell, D., Naramura, M., Gu, H., Band, V., Band, H. (2003). Cbl-mediated Ubiquitinylation Is Required for Lysosomal Sorting of Epidermal Growth Factor Receptor but Is Dispensable for Endocytosis. J. Biol. Chem. 278: 28950-28960 [Abstract] [Full Text]  
  • Duval, M., Bedard-Goulet, S., Delisle, C., Gratton, J.-P. (2003). Vascular Endothelial Growth Factor-dependent Down-regulation of Flk-1/KDR Involves Cbl-mediated Ubiquitination: CONSEQUENCES ON NITRIC OXIDE PRODUCTION FROM ENDOTHELIAL CELLS. J. Biol. Chem. 278: 20091-20097 [Abstract] [Full Text]  
  • Scaife, R. M., Courtneidge, S. A., Langdon, W. Y. (2003). The multi-adaptor proto-oncoprotein Cbl is a key regulator of Rac and actin assembly. J. Cell Sci. 116: 463-473 [Abstract] [Full Text]  
  • Wang, Y., Miao, H., Li, S., Chen, K.-D., Li, Y.-S., Yuan, S., Shyy, J. Y.-J., Chien, S. (2002). Interplay between integrins and FLK-1 in shear stress-induced signaling. Am. J. Physiol. Cell Physiol. 283: C1540-C1547 [Abstract] [Full Text]  
  • Taher, T. E. I., Tjin, E. P. M., Beuling, E. A., Borst, J., Spaargaren, M., Pals, S. T. (2002). c-Cbl Is Involved in Met Signaling in B Cells and Mediates Hepatocyte Growth Factor-Induced Receptor Ubiquitination. J. Immunol. 169: 3793-3800 [Abstract] [Full Text]  
  • Haglund, K., Shimokawa, N., Szymkiewicz, I., Dikic, I. (2002). Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors. Proc. Natl. Acad. Sci. USA 99: 12191-12196 [Abstract] [Full Text]  
  • Freywald, A., Sharfe, N., Roifman, C. M. (2002). The Kinase-null EphB6 Receptor Undergoes Transphosphorylation in a Complex with EphB1. J. Biol. Chem. 277: 3823-3828 [Abstract] [Full Text]  
  • Dankort, D., Jeyabalan, N., Jones, N., Dumont, D. J., Muller, W. J. (2001). Multiple ErbB-2/Neu Phosphorylation Sites Mediate Transformation through Distinct Effector Proteins. J. Biol. Chem. 276: 38921-38928 [Abstract] [Full Text]  
  • Sanjay, A., Houghton, A., Neff, L., DiDomenico, E., Bardelay, C., Antoine, E., Levy, J., Gailit, J., Bowtell, D., Horne, W. C., Baron, R. (2001). Cbl Associates with Pyk2 and Src to Regulate Src Kinase Activity, {alpha}v{beta}3 Integrin-Mediated Signaling, Cell Adhesion, and Osteoclast Motility. JCB 152: 181-196 [Abstract] [Full Text]  
  • Fournier, T. M., Lamorte, L., Maroun, C. R., Lupher, M., Band, H., Langdon, W., Park, M. (2000). Cbl-transforming Variants Trigger a Cascade of Molecular Alterations That Lead to Epithelial Mesenchymal Conversion. Mol. Biol. Cell 11: 3397-3410 [Abstract] [Full Text]  
  • Rao, N., Lupher, M. L. Jr., Ota, S., Reedquist, K. A., Druker, B. J., Band, H. (2000). The Linker Phosphorylation Site Tyr292 Mediates the Negative Regulatory Effect of Cbl on ZAP-70 in T Cells. J. Immunol. 164: 4616-4626 [Abstract] [Full Text]  
  • Andoniou, C. E., Lill, N. L., Thien, C. B., Lupher, M. L. Jr., Ota, S., Bowtell, D. D. L., Scaife, R. M., Langdon, W. Y., Band, H. (2000). The Cbl Proto-Oncogene Product Negatively Regulates the Src-Family Tyrosine Kinase Fyn by Enhancing Its Degradation. Mol. Cell. Biol. 20: 851-867 [Abstract] [Full Text]  
  • Lill, N. L., Douillard, P., Awwad, R. A., Ota, S., Lupher, M. L. Jr., Miyake, S., Meissner-Lula, N., Hsu, V. W., Band, H. (2000). The Evolutionarily Conserved N-terminal Region of Cbl Is Sufficient to Enhance Down-regulation of the Epidermal Growth Factor Receptor. J. Biol. Chem. 275: 367-377 [Abstract] [Full Text]  
  • Ota, S., Hazeki, K., Rao, N., Lupher, M. L. Jr., Andoniou, C. E., Druker, B., Band, H. (2000). The RING Finger Domain of Cbl Is Essential for Negative Regulation of the Syk Tyrosine Kinase. J. Biol. Chem. 275: 414-422 [Abstract] [Full Text]  
  • Scaife, R., Langdon, W. (2000). c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology. J. Cell Sci. 113: 215-226 [Abstract]  
  • Sato, N., Kim, M.-K., Schreiber, A. D. (1999). Enhancement of Fc{gamma} Receptor-Mediated Phagocytosis by Transforming Mutants of Cbl. J. Immunol. 163: 6123-6131 [Abstract] [Full Text]  
  • Yokouchi, M., Kondo, T., Houghton, A., Bartkiewicz, M., Horne, W. C., Zhang, H., Yoshimura, A., Baron, R. (1999). Ligand-induced Ubiquitination of the Epidermal Growth Factor Receptor Involves the Interaction of the c-Cbl RING Finger and UbcH7. J. Biol. Chem. 274: 31707-31712 [Abstract] [Full Text]  
  • Bartkiewicz, M., Houghton, A., Baron, R. (1999). Leucine Zipper-mediated Homodimerization of the Adaptor Protein c-Cbl. A ROLE IN c-Cbl's TYROSINE PHOSPHORYLATION AND ITS ASSOCIATION WITH EPIDERMAL GROWTH FACTOR RECEPTOR. J. Biol. Chem. 274: 30887-30895 [Abstract] [Full Text]  
  • van Leeuwen, J. E. M., Paik, P. K., Samelson, L. E. (1999). The Oncogenic 70Z Cbl Mutation Blocks the Phosphotyrosine Binding Domain-Dependent Negative Regulation of ZAP-70 by c-Cbl in Jurkat T Cells. Mol. Cell. Biol. 19: 6652-6664 [Abstract] [Full Text]  
  • Miyake, S., Mullane-Robinson, K. P., Lill, N. L., Douillard, P., Band, H. (1999). Cbl-mediated Negative Regulation of Platelet-derived Growth Factor Receptor-dependent Cell Proliferation. A CRITICAL ROLE FOR Cbl TYROSINE KINASE-BINDING DOMAIN. J. Biol. Chem. 274: 16619-16628 [Abstract] [Full Text]  
  • Zhang, Z., Elly, C., Altman, A., Liu, Y.-C. (1999). Dual Regulation of T Cell Receptor-mediated Signaling by Oncogenic Cbl Mutant 70Z. J. Biol. Chem. 274: 4883-4889 [Abstract] [Full Text]  
  • van Leeuwen, J. E. M., Paik, P. K., Samelson, L. E. (1999). Activation of Nuclear Factor of Activated T Cells-(NFAT) and Activating Protein 1 (AP-1) by Oncogenic 70Z Cbl Requires an Intact Phosphotyrosine Binding Domain but Not Crk(L) or p85 Phosphatidylinositol 3-Kinase Association. J. Biol. Chem. 274: 5153-5162 [Abstract] [Full Text]  
  • Saci, A., Pain, S., Rendu, F., Bachelot-Loza, C. (1999). Fc Receptor-mediated Platelet Activation Is Dependent on Phosphatidylinositol 3-Kinase Activation and Involves p120cbl. J. Biol. Chem. 274: 1898-1904 [Abstract] [Full Text]  
  • Lupher Jr., M. L., Rao, N., Lill, N. L., Andoniou, C. E., Miyake, S., Clark, E. A., Druker, B., Band, H. (1998). Cbl-mediated Negative Regulation of the Syk Tyrosine Kinase. A CRITICAL ROLE FOR Cbl PHOSPHOTYROSINE-BINDING DOMAIN BINDING TO Syk PHOSPHOTYROSINE 323. J. Biol. Chem. 273: 35273-35281 [Abstract] [Full Text]  
  • Chu, J., Liu, Y., Koretzky, G. A., Durden, D. L. (1998). SLP-76-Cbl-Grb2-Shc Interactions in Fcgamma RI Signaling. Blood 92: 1697-1706 [Abstract] [Full Text]  
  • Murphy, M. A., Schnall, R. G., Venter, D. J., Barnett, L., Bertoncello, I., Thien, C. B. F., Langdon, W. Y., Bowtell, D. D. L. (1998). Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice. Mol. Cell. Biol. 18: 4872-4882 [Abstract] [Full Text]  
  • Miyake, S., Lupher, M. L. Jr., Druker, B., Band, H. (1998). The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor alpha. Proc. Natl. Acad. Sci. USA 95: 7927-7932 [Abstract] [Full Text]  
  • Gesbert, F., Garbay, C., Bertoglio, J. (1998). Interleukin-2 Stimulation Induces Tyrosine Phosphorylation of p120-Cbl and CrkL and Formation of Multimolecular Signaling Complexes in T Lymphocytes and Natural Killer Cells. J. Biol. Chem. 273: 3986-3993 [Abstract] [Full Text]  
  • Lupher Jr., M. L., Songyang, Z., Shoelson, S. E., Cantley, L. C., Band, H. (1997). The Cbl Phosphotyrosine-binding Domain Selects a D(N/D)XpY Motif and Binds to the Tyr292 Negative Regulatory Phosphorylation Site of ZAP-70. J. Biol. Chem. 272: 33140-33144 [Abstract] [Full Text]  
  • Baron, V., Schwartz, M. (2000). Cell Adhesion Regulates Ubiquitin-mediated Degradation of the Platelet-derived Growth Factor Receptor beta. J. Biol. Chem. 275: 39318-39323 [Abstract] [Full Text]  
  • Hamilton, E., Miller, K. M., Helm, K. M., Langdon, W. Y., Anderson, S. M. (2001). Suppression of Apoptosis Induced by Growth Factor Withdrawal by an Oncogenic Form of c-Cbl. J. Biol. Chem. 276: 9028-9037 [Abstract] [Full Text]  
  • Yokouchi, M., Kondo, T., Sanjay, A., Houghton, A., Yoshimura, A., Komiya, S., Zhang, H., Baron, R. (2001). Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins. J. Biol. Chem. 276: 35185-35193 [Abstract] [Full Text]  
  • Shishido, T., Akagi, T., Ouchi, T., Georgescu, M.-M., Langdon, W. Y., Hanafusa, H. (2000). The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation. Proc. Natl. Acad. Sci. USA 97: 6439-6444 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»