ABB  Vol.4 No.12 , December 2013
The Cbl family of ubiquitin ligases regulates FcεRI expression and mast cell activation
ABSTRACT

Antigen interaction with specific IgE bound to the high-affinity Fc receptor for IgE, constitutively expressed on the cell-surface of mast cells, generates signals that cause a shift in the resting state equilibrium of phosphorylation and dephosphorylation events that serves to maintain homeostasis. The outcome of this activated state is the release of a wide array of preformed and newly synthesized pro-inflammatory mediators. During the past few years, the existence of a negative feedback loop initiated upon FcεRI engagement has also been envisaged. This negative signal involves the coordinated action of adaptors, phosphatases and ubiquitin ligases that limits the intensity and duration of positive signals, thus modulating mast cell functions. Relevant to this, others and we have demonstrated that Cbl family proteins control the amplitude of FcεRI-generated signals by specific ubiquitin modification of activated receptor subunits and associated protein tyrosine kinases. In this article, we review advances in our understanding of the molecular mechanisms through which Cbl proteins regulate FcεRI expression and signaling.


Cite this paper
Molfetta, R. , Gasparrini, F. , Santoni, A. and Paolini, R. (2013) The Cbl family of ubiquitin ligases regulates FcεRI expression and mast cell activation. Advances in Bioscience and Biotechnology, 4, 1063-1072. doi: 10.4236/abb.2013.412142.
References
[1]   Galli, S.J. (2000) Mast cells and basophils. Current Opinion in Hematology, 7, 32-39.
http://dx.doi.org/10.1097/00062752-200001000-00007

[2]   Prussin, C. and Metcalfe, D.D. (2003) IgE, mast cells, basophils, and eosinophils. Journal of Allergy and Clinical Immunology, 111, 486-494.
http://dx.doi.org/10.1067/mai.2003.120

[3]   Siraganian, R.P. (2003) Mast cell signal transduction from the high-affinity IgE receptor. Current Opinion Immunology, 15, 639-646.
http://dx.doi.org/10.1016/j.coi.2003.09.010

[4]   Kraft, S. and Kinet, J.P. (2007) New developments in FcεRI regulation, function and inhibition. Nature Reviews Immunology, 7, 365-378.
http://dx.doi.org/10.1038/nri2072

[5]   Falcone, F.H., Haas, H. and Gibbs, B.F. (2000) The human basophil: A new appreciation of its role in immune responses. Blood, 96, 4028-4038.

[6]   MacGlashan Jr., D.W. (2008) IgE receptor and signal transduction in mast cells and basophils. Current Opinion Immunology, 20, 717-723.
http://dx.doi.org/10.1016/j.coi.2008.08.004

[7]   Molfetta, R., Peruzzi, G., Santoni, A. and Paolini, R. (2007) Negative signals from FcεRI engagement attenuate mast cell functions. Archivum Immunologiae et Therapiae Experimentalis, 55, 219-229.
http://dx.doi.org/10.1007/s00005-007-0028-4

[8]   Thien, C.B. and Langdon, W.Y. (2001). Cbl: Many adaptations to regulate protein tyrosine kinases. Nature Reviews in Molecular Cell Biology, 2, 294-307.
http://dx.doi.org/10.1038/35067100

[9]   Rao, N., Dodge, I. and Band, H. (2002) The Cbl family of ubiquitin ligases: Critical negative regulators of tyrosine kinase signaling in the immune system. Journal of Leukocyte Biology, 71, 753-763.

[10]   Dikic, I., Szymkiewicz, I. and Soubeyran, P. (2003) Cbl signaling networks in the regulation of cell function. Cellular and Molecular Life Science, 60, 1805-1827.
http://dx.doi.org/10.1007/s00018-003-3029-4

[11]   Swaminathan, G. and Tsygankov, A.Y. (2006) The Cbl family proteins: Ring leaders in regulation of cell signaling. Journal of Cellular Physiology, 209, 21-43.
http://dx.doi.org/10.1002/jcp.20694

[12]   Paolini, R., Molfetta, R., Beitz, L.O., Zhang, J., Scharenberg, A.M., Piccoli, M., Frati, L., Siraganian, R. and Santoni, A. (2002) Activation of Syk tyrosine kinase is required for c-Cbl-mediated ubiquitination of FcεRI and Syk in RBL cells. Journal of Biological Chemistry, 277, 36940-36947. http://dx.doi.org/10.1074/jbc.M204948200

[13]   Kyo, S., Sada, K., Qu, X., Maeno, K., Shahjahan Miah, S.M., Kawauchi-Kamata, K. and Yamamura, H. (2003) Negative regulation of Lyn protein-tyrosine kinase by cCbl ubiquitin-protein ligase in FcεRI-mediated mast cell activation. Genes Cells, 8, 825-836.
http://dx.doi.org/10.1046/j.1365-2443.2003.00679.x

[14]   Qu, X., Sada, K., Kyo, S., Maeno, K., Miah, S.M. and Yamamura, H. (2004) Negative regulation of FcεRI-mediated mast cell activation by the ubiquitin-protein ligase Cbl-b. Blood, 103, 1779-1786.
http://dx.doi.org/10.1182/blood-2003-07-2260

[15]   Lin, S., Cicala, C., Scharenberg, A.M. and Kinet J.P. (1996) The FcεRI subunit functions as an amplifier of FcεRI-mediated cell activation signals. Cell, 85, 985-995.
http://dx.doi.org/10.1016/S0092-8674(00)81300-8

[16]   Simons, K. and Toomre, D. (2000) Lipid rafts and signal transduction. Nature Reviews in Molecular Cell Biology, 1, 31-39. http://dx.doi.org/10.1038/35036052

[17]   Field, K.A., Holowka, D. and Baird, B. (1997) Compartmentalized activation of the high affinity immunoglobulin E receptor within membrane domains. Journal of Biological Chemistry, 272, 4276-4280.
http://dx.doi.org/10.1074/jbc.272.7.4276

[18]   Sheets, E.D., Holowka, D. and Baird, B. (1999) Critical role for cholesterol in Lyn-mediated tyrosine phosphorylation of FcεRI and their association with detergent-resistant membranes. Journal of Cell Biology, 145, 877-887. http://dx.doi.org/10.1083/jcb.145.4.877

[19]   Young, R.M., Holowka, D. and Baird, B. (2003) A lipid raft environment enhances Lyn kinase activity by protecting the active site tyrosine from dephosphorylation. Journal of Biological Chemistry, 278, 20746-20752.
http://dx.doi.org/10.1074/jbc.M211402200

[20]   Oliver, J.M., Burg, D.L., Wilson, B.S., McLaughlin, J.L. and Geahlen, R.L. (1994) Inhibition of mast cell FcεR1-mediated signalling and effector function by the Syk-selective inhibitor, piceatannol. Journal of Biological Chemistry, 269, 29697-29703.

[21]   Costello, P.S., Turner, M., Walters, A.E., Cunningham, C.N., Bauer, P.H., Downward, J. and Tybulewicz, V.L. (1996) Critical role for the tyrosine kinase Syk in signaling through the high affinity IgE receptor of mast cells. Oncogene, 13, 2595-2605.

[22]   Zhang, J., Berenstein, E.H., Evans, R.L. and Siraganian, R.P. (1996) Transfection of Syk protein tyrosine kinase reconstitutes high affinity IgE receptor-mediated degranulation in a Syk-negative variant of rat basophilic leukemia RBL-2H3 cells. Journal of Experimental Medicine, 184, 71-79. http://dx.doi.org/10.1084/jem.184.1.71

[23]   Moriya, K., Rivera, J., Odom, S., Sakuma, Y., Muramato, K., Yoshiuchi, T., Miyamoto, M. and Yamada, K. (1997) ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of Fcepsilon receptor I-mediated activation of Syk. Proceeding of the National Academy of Sciences USA, 94, 12539-12544.
http://dx.doi.org/10.1073/pnas.94.23.12539

[24]   Kepley, C.L., Youssef, L., Andrews, R.P., Wilson, B.S. and Oliver, J.M. (1999) Syk deficiency in nonreleaser basophils. Journal of Allergy and Clinical Immunology, 104, 279-284.
http://dx.doi.org/10.1016/S0091-6749(99)70367-2

[25]   Lavens-Phillips, S.E. and MacGlashan Jr., D.W. (2000) The tyrosine kinases p53/56lyn and p72syk are differentially expressed at the protein level but not at the messenger RNA level in nonreleasing human basophils. American Journal of Respiratory Cell and Molecular Biology, 23, 566-571.
http://dx.doi.org/10.1165/ajrcmb.23.4.4123

[26]   Parravicini, V., Gadina, M., Kovarova, M., Odom, S., Gonzalez-Espinosa, C., Furumoto, Y., Saitoh, S., Samelson, L.E., O’Shea, J.J. and Rivera, J. (2002) Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nature Immunology, 3, 741-748.

[27]   Daëron, M., Jaeger, S., Du Pasquier, L. and Vivier, E. (2008) Immunoreceptor tyrosine-based inhibition motifs: A quest in the past and future. Immunological Reviews, 224, 11-43.
http://dx.doi.org/10.1111/j.1600-065X.2008.00666.x

[28]   Kepley, C.L., Cambier, J.C., Morel, P.A., Lujan, D., Ortega, E., Wilson, B.S. and Oliver, J.M. (2000) Negative regulation of FcεRI signaling by FcγRII costimulation in human blood basophils. Journal of Allergy and Clinical Immunology, 106, 337-348.
http://dx.doi.org/10.1067/mai.2000.107931

[29]   Kimura, T., Zhang, J., Sagawa, K., Sakaguchi, K., Appella, E. and Siraganian, R.P. (1997) Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor. Journal of Immunology, 159, 4426-4434.

[30]   Kimura, T., Sakamoto, H., Appella, E. and Siraganian, R.P. (1997) The negative signaling molecule SH2 domain-containing inositol-polyphosphate 5-phosphatase (SHIP) binds to the tyrosine-phosphorylated beta subunit of the high affinity IgE receptor. Journal of Biological Chemistry, 272, 13991-13996.
http://dx.doi.org/10.1074/jbc.272.21.13991

[31]   Leung, W.H. and Bolland S. (2007) The inositol 5’-phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation and cytokine production. Journal of Immunology, 179, 95-102.

[32]   Vonakis, B.M., Gibbons Jr., S., Sora, R., Langdon, J.M. and MacDonald, S.M. (2001) Src homology 2 domaincontaining inositol 5’ phosphatase is negatively associated with histamine release to human recombinant histamine-releasing factor in human basophils. Journal of Allergy and Clinical Immunology, 108, 822-831.
http://dx.doi.org/10.1067/mai.2001.119159

[33]   Furumoto, Y., Brooks, S., Olivera, A., Takagi, Y., Miyagishi, M., Taira, K., Casellas, R., Beaven, M.A., Gilfillan, A.M. and Rivera, J. (2006) Cutting Edge: Lentiviral short hairpin RNA silencing of PTEN in human mast cells reveals constitutive signals that promote cytokine secretion and cell survival. Journal of Immunology, 176, 5167-5171.

[34]   Thien, C.B. and Langdon, W.Y. (2005) c-Cbl and Cbl-b ubiquitin ligases: Substrate diversity and the negative regulation of signalling responses. Biochemical Journal, 391, 153-166. http://dx.doi.org/10.1042/BJ20050892

[35]   Meng, W., Sawasdikosol, S., Burakoff, S.J. and Eck, M.J. (1999) Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature, 398, 84-90. http://dx.doi.org/10.1038/18050

[36]   Zheng, N., Wang, P., Jeffrey, P.D. and Pavletich, N.P. (2000) Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases. Cell, 102, 533-539. http://dx.doi.org/10.1016/S0092-8674(00)00057-X

[37]   Joazeiro, C.A. and Weissman, A.M. (2000) RING finger proteins: Mediators of ubiquitin ligase activity. Cell, 102, 549-552. http://dx.doi.org/10.1016/S0092-8674(00)00077-5

[38]   Ciechanover, A. (1998) The ubiquitin-proteasome pathway: On protein death and cell life. EMBO Journal, 17, 7151-7160. http://dx.doi.org/10.1093/emboj/17.24.7151

[39]   Laney, J.D. and Hochstrasser, M. (1999) Substrate targeting in the ubiquitin system. Cell, 97, 427-430.
http://dx.doi.org/10.1016/S0092-8674(00)80752-7

[40]   Weissman, A.M. (2001) Themes and variations on ubiquitylation. Nature Reviews. Molecular Cell Biology, 2, 169-178. http://dx.doi.org/10.1038/35056563

[41]   Kassenbrock, C.K. and Anderson, S.M. (2004) Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations. Journal of Biological Chemistry, 279, 28017-28027.
http://dx.doi.org/10.1074/jbc.M404114200

[42]   Thrower, J.S., Hoffman, L., Rechesteiner, M. and Pickart, C.M. (2000) Recognition of the polyubiquitin proteolytic signal. EMBO Journal, 19, 94-102.
http://dx.doi.org/10.1093/emboj/19.1.94

[43]   Hicke, L. and Dunn, R. (2003) Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annual Review of Cell and Developmental Biology, 19, 141-172.
http://dx.doi.org/10.1146/annurev.cellbio.19.110701.154617

[44]   Haglund, K., Sigismund, S., Polo, S., Szymkiewicz, I., Di Fiore, P.P. and Dikic, I. (2003) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nature Cell Biology, 5, 461-466.
http://dx.doi.org/10.1038/ncb983

[45]   Mosesson, Y., Shtiegman, K., Katz, M., Zwang, Y., Vereb, G., Szollosi, J. and Yarden, Y. (2003) Endocytosis of receptor tyrosine kinases is driven by mono-, not poly-ubiquitylation. Journal of Biological Science, 278, 31323-31326.

[46]   Katkere, B., Rosa, S. and Drake, J. R. (2012) The Sykbinding ubiquitin ligase c-Cbl mediates signaling-dependent B cell receptor ubiquitination and B cell receptor-mediated antigen processing and presentation. Journal of Biological Chemistry, 287, 16636-16644.
http://dx.doi.org/10.1074/jbc.M112.357640

[47]   Wang, H.Y., Altman, Y., Fang, D., Dai, Y., Shao, Y. and Liu, Y.C. (2001) Cbl promotes ubiquitination of the T cell receptor through an adaptor function of Zap-70. Journal of Biological Chemistry, 276, 26004-26011.
http://dx.doi.org/10.1074/jbc.M010738200

[48]   Ota, Y., Beitz, L.O., Scharenberg, A.M., Donovan, J.A., Kinet, J.P. and Samelson, L.E. (1996) Characterization of Cbl tyrosine phosphorylation and a Cbl-Syk complex in RBL-2H3 cells. Journal of Experimental Medicine, 184, 1713-1723. http://dx.doi.org/10.1084/jem.184.5.1713

[49]   Zhang, J., Chiang, Y.J., Hodes, R.J. and Siraganian, R.P. (2004) Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor. Journal of Immunology, 173, 1811-1818.

[50]   Lafont, F. and Simons, K. (2001) Raft-partititioning of the ubiquitin ligases Cbl and Nedd4 upon IgE-triggered cell signaling. Proceeding of the National Academy of Sciences of the United States of America, 98, 3180-3184.
http://dx.doi.org/10.1073/pnas.051003498

[51]   Suzuki, H., Takei, M., Yanagida, M., Nakahata, T., Kawakami, T. and Fukamachi, H. (1997) Early and late events in Fc epsilon RI signal transduction in human cultured mast cells. Journal of Immunology, 159, 5881-5888.

[52]   Macglashan, D. and Miura, K. (2004) Loss of syk kinase during IgE-mediated stimulation of human basophils. Journal of Allergy and Clinical Immunology, 114, 1317-1324. http://dx.doi.org/10.1016/j.jaci.2004.08.037

[53]   Ota, Y. and Samelson, L.E. (1997) The product of the proto-oncogene c-cbl: A negative regulator of the Syk tyrosine kinase. Science, 276, 418-420.
http://dx.doi.org/10.1126/science.276.5311.418

[54]   Paolini, R. and Kinet, J.P. (1993) Cell surface control of the multiubiquitination and deubiquitination of high-affinity immunoglobulin E receptors. EMBO Journal, 12, 779-786.

[55]   Molfetta, R., Gasparrini, F., Peruzzi, G., Vian, L., Piccoli, M., Frati, L., Santoni, A. and Paolini, R. (2009) Lipid raft-dependent FcεRI ubiquitination regulates receptor endocytosis through the action of Ubiquitin Binding Adaptors. PLoS ONE, 4, Article ID: e5604.
http://dx.doi.org/10.1371/journal.pone.0005604

[56]   Molfetta, R., Gasparrini, F., Santoni, A. and Paolini. R. (2010) Ubiquitination and endocytosis of the high affinity receptor for IgE. Molecular Immunology, 47, 2427-2434. http://dx.doi.org/10.1016/j.molimm.2010.06.003

[57]   Carbone, R., Fré, S., Iannolo, G., Belleudi, F., Mancini, P., Pelicci, P.G., Torrisi, M.R. and Di Fiore, P.P. (1997) Eps15 and eps15R are essential components of the endocytic pathway. Cancer Research, 57, 5498-5504.

[58]   Chen, H., Fre, S., Slepnev, V.I., Capua, M.R., Takei, K., Butler, M.H., Di Fiore, P.P. and De Camilli, P. (1998) Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature, 394, 793-797.
http://dx.doi.org/10.1038/28660

[59]   Raiborg, C., Bache, K.G., Gillooly, D.J., Madshus, I.H., Stang, E. and Stenmark, H. (2002) Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nature Cell Biology, 4, 394-398.
http://dx.doi.org/10.1038/ncb791

[60]   Fattakhova, G., Masilamani, M., Borrego, F., Gilfillan, A.M., Metcalfe, D.D. and Coligan, J.E. (2006) The highaffinity immunoglobulin-E receptor (FcεRI) is endocytosed by an AP-2/clathrin-independent, dynamin-dependent mechanism. Traffic, 7, 673-685.
http://dx.doi.org/10.1111/j.1600-0854.2006.00423.x

[61]   Gasparrini, F., Molfetta, R., Quatrini, L., Frati, L., Santoni, A. and Paolini, R. (2012) Syk-dependent regulation of Hrs phosphryaltion and ubiquitination upon FcεRI engagement: impact on Hrs membrane/cytosol localization. European Journal of Immunology, 42, 2744-2753.
http://dx.doi.org/10.1002/eji.201142278

[62]   Hoeller, D., Crosetto, N., Blagoev, B., Raiborg, C., Tikkanen, R., Wagner, S., Kowanetz, K., Breitling, R., Mann, M., Stenmark, H. and Dikic, I. (2006) Regulation of ubiquitin-binding proteins by monoubiquitination. Nature Cell Biology, 8, 163-169.
http://dx.doi.org/10.1038/ncb1354

[63]   Gustin, S.E., Thien, C.B. and Langdon, W.Y. (2006) Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells. Journal of Immunology, 177, 5980-5989.

[64]   Oksvold, M.P., Dagger, S.A., Thien, C.B. and Langdon, W.Y. (2008) The Cbl-b RING finger domain has a limited role in regulating inflammatory cytokine production by IgE-activated mast cells. Molecular Immunology, 45, 925-936. http://dx.doi.org/10.1016/j.molimm.2007.08.002

[65]   Andoniou, C.E., Lill, N.L., Thien, C.B., Lupher Jr., M.L., Ota, S., Bowtell, D.D.L., Scaife, R.M., Langdon, W.Y. and Band, H. (2000) The Cbl proto-oncogene product negatively regulates the Src-family tyrosine kinase Fyn by enhancing its degradation. Molecular Cell Biology, 20, 851-867.
http://dx.doi.org/10.1128/MCB.20.3.851-867.2000

[66]   Rao, N., Ghosh, A.K., Ota, S., Zhou, P.C., Reddi, A.L., Hakezi, K., Druker, B.K., Wu, J. and Band, H. (2001). The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquitylation upon B-cell receptor stimulation. EMBO Journal, 20, 7085-7095.
http://dx.doi.org/10.1093/emboj/20.24.7085

[67]   Rao, N., Miyake, S., Reddi, A.L., Douillard, P., Ghosh, A.K., Dodge, I.L., Zhou, P., Fernandes, N.D. and Band, H. (2002) Negative regulation of Lck by Cbl ubiquitin ligase. Proceeding of the National Academy of Sciences USA, 99, 3794-3799.

[68]   Sohn, H.W., Gu, H. and Pierce, S.K. (2003) Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. Journal of Experimental Medicine, 197, 1511-1524. http://dx.doi.org/10.1084/jem.20021686

[69]   Youssef, L.A., Wilson, B.S. and Oliver, J.M. (2002) Proteasome-dependent regulation of Syk tyrosine kinase levels in human basophils. Journal of Allergy and Clinical Immunology, 110, 366-373.
http://dx.doi.org/10.1067/mai.2002.127562

[70]   Peruzzi, G., Molfetta, R., Gasparrini, F., Vian, L., Morrone, S., Piccoli, M., Frati, L., Santoni, A. and Paolini, R. (2007) The adaptor molecule CIN85 regulates Syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. Journal of Immunology, 179, 2089-2096.

[71]   MacGlashan Jr., D.W., Ishmael, S., MacDonald, S.M., Langdon, J.M., Arm, J.P. and Slogane, D.E. (2008) Induced loss of Syk in human basophils by non-IgE-dependent stimuli. Journal of Immunology, 180, 4208-4217.

 
 
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