CBL (gene) explained

Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene family. CBL gene, a part of the Cbl family, encodes the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.^[1]

Discovery

In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered^[2] and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a mouse-tropic strain of Murine leukemia virus isolated from the brain of a mouse captured at Lake Casitas, California known as Cas-Br-M,^[3] and was found to have excised approximately a third of the original c-Cbl gene from a mouse into which it was injected. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumor formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.

Structure

Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:

• N-terminal tyrosine kinase binding domain (TKB domain): determines the protein which it can bind to
• RING finger domain motif: recruits enzymes involved in ubiquitination
• Proline-rich region: the site of interaction between Cbl and cytosolic proteins involved in Cbl's adaptor functions
• C-terminal ubiquitin-associated domain (UBA domain): the site of ubiquitin binding

This domain structure and the tyrosine and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.^[4]

Homologues

Three mammalian homologues have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:

1. c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
2. Cbl-b: ubiquitously expressed, 982 amino acids long.
3. Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.

Both c-Cbl and Cbl-b have orthologues in D. melanogaster (D-Cbl) and C. elegans (Sli-1), hinting at a long evolutionary path for these proteins.

Function

Ubiquitin ligase

Ubiquitination is the process of chemically attaching ubiquitin monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligases. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome for degradation.

Interactions

Cbl gene has been shown to interact with:

• Abl gene,^[5]
• ARHGEF7,^[6]
• C-Met,^[7]
• CD2AP,^{[8] [9]}
• CSF1R.^[10]
• CRK,^[11]
• CRKL,^{[12] [13] [14] [15] [16] [17] [18]}
• EGFR,<^{[19] [20]}
• FRS2,^[21]
• FYN,^{[15] [22]}
• Grb2,^{[11] [21] [23] [24] [25] [26] [27] [28] [29]}
• HCK,^{[30] [31]}
• IGF1R,^[32]
• LCP2;,^{[33] [34]}
• NCK1,^{[35] [33]}
• PDGFRA,^[36]
• PIK3R1,^{[37] [38] [39]}
• PIK3R2,^{[12] [40]}
• PLCG1,^{[19] [41]}
• PTK2B,^{[42] [43]}
• PTPN11,^[44]
• SH2B2,^{[45] [46]}
• SH3KBP1^{[7] [47] [48] [49] [50]}
• SHC1,^{[37] [51]}
• SLA2,^[52]
• SORBS1,^{[42] [53]}
• SORBS2,^{[5] [42]}
• SPRY2,^{[45] [54]}
• Syk,^{[55] [56] [57]}
• UBE2L3,^{[58] [59] [60]}
• VAV1,^{[56] [61]}
• YWHAB,^[26]
• YWHAQ,^{[62] [63]} and
• ZAP-70,^{[64] [65]}

Further reading

• Smit L, Borst J . The Cbl family of signal transduction molecules . Crit Rev Oncog . 8 . 4 . 359–79 . 1997 . 9622055 . 10.1615/critrevoncog.v8.i4.50 .
• Lupher ML, Andoniou CE, Bonita D, Miyake S, Band H . The c-Cbl oncoprotein . Int. J. Biochem. Cell Biol. . 30 . 4 . 439–44 . 1998 . 9675877 . 10.1016/S1357-2725(97)00075-7 .
• Fang N, Fang D, Wang HY, Altman A, Liu YC . Regulation of immune responses by E3 ubiquitin-protein ligases . Curr. Dir. Autoimmun. . 5 . 161–75 . 2002 . 11826757 . 10.1159/000060552 . Current Directions in Autoimmunity . 3-8055-7308-1 .

External links

• Quips article describing CBL function at PDBe
• OMIM entries on NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA and CBL

Notes and References

1. Naramura M, Nadeau S, Mohapatra B, Ahmad G, Mukhopadhyay C, Sattler M, Raja SM, Natarajan A, Band V, Band H . Mutant Cbl proteins as oncogenic drivers in myeloproliferative disorders . Oncotarget . 2 . 3 . 245–50 . 2011 . 21422499 . 3134300 . 10.18632/oncotarget.233.
2. Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HC . v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas . Proc. Natl. Acad. Sci. U.S.A. . 86 . 4 . 1168–72 . 1989 . 2784003 . 286647 . 10.1073/pnas.86.4.1168 . 1989PNAS...86.1168L . free .
3. Hartley . JW . Rowe . WP . Naturally occurring murine leukemia viruses in wild mice: characterization of a new "amphotropic" class. . Journal of Virology . July 1976 . 19 . 1 . 21 . 10.1128/JVI.19.1.19-25.1976 . 59816 . 354828.
4. Schmidt MH, Dikic I . The Cbl interactome and its functions . Nat. Rev. Mol. Cell Biol. . 6 . 12 . 907–18 . 2005 . 16227975 . 10.1038/nrm1762 . 1527924 .
5. Soubeyran P, Barac A, Szymkiewicz I, Dikic I . Cbl-ArgBP2 complex mediates ubiquitination and degradation of c-Abl . Biochem. J. . 370 . Pt 1 . 29–34 . February 2003 . 12475393 . 1223168 . 10.1042/BJ20021539 .
6. Flanders JA, Feng Q, Bagrodia S, Laux MT, Singavarapu A, Cerione RA . The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins . FEBS Lett. . 550 . 1–3 . 119–23 . August 2003 . 12935897 . 10.1016/S0014-5793(03)00853-6 . 46540220 .
7. Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S . The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met . Nature . 416 . 6877 . 187–90 . March 2002 . 11894096 . 10.1038/416187a . 2002Natur.416..187P . 4389099 .
8. Kirsch KH, Georgescu MM, Shishido T, Langdon WY, Birge RB, Hanafusa H . The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction . J. Biol. Chem. . 276 . 7 . 4957–63 . February 2001 . 11067845 . 10.1074/jbc.M005784200 . free .
9. Cormont M, Metón I, Mari M, Monzo P, Keslair F, Gaskin C, McGraw TE, Le Marchand-Brustel Y . CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl . Traffic . 4 . 2 . 97–112 . February 2003 . 12559036 . 10.1034/j.1600-0854.2003.40205.x . 38612642 .
10. Mancini A, Koch A, Wilms R, Tamura T . c-Cbl associates directly with the C-terminal tail of the receptor for the macrophage colony-stimulating factor, c-Fms, and down-modulates this receptor but not the viral oncogene v-Fms . J. Biol. Chem. . 277 . 17 . 14635–40 . April 2002 . 11847211 . 10.1074/jbc.M109214200 . free .
11. Husson H, Mograbi B, Schmid-Antomarchi H, Fischer S, Rossi B . CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2 . Oncogene . 14 . 19 . 2331–8 . May 1997 . 9178909 . 10.1038/sj.onc.1201074 . 967748 .
12. Lin H, Martelli MP, Bierer BE . The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation . Int. Immunol. . 13 . 1 . 13–22 . January 2001 . 11133830 . 10.1093/intimm/13.1.13 . free .
13. Kyono WT, de Jong R, Park RK, Liu Y, Heisterkamp N, Groffen J, Durden DL . Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI) . J. Immunol. . 161 . 10 . 5555–63 . November 1998 . 10.4049/jimmunol.161.10.5555 . 9820532 . 255369788 . free .
14. Park RK, Kyono WT, Liu Y, Durden DL . CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling . J. Immunol. . 160 . 10 . 5018–27 . May 1998 . 10.4049/jimmunol.160.10.5018 . 9590251 . 9556579 . free .
15. Taher TE, Tjin EP, Beuling EA, Borst J, Spaargaren M, Pals ST . c-Cbl is involved in Met signaling in B cells and mediates hepatocyte growth factor-induced receptor ubiquitination . J. Immunol. . 169 . 7 . 3793–800 . October 2002 . 12244174 . 10.4049/jimmunol.169.7.3793 . free .
16. Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, Griffin JD . Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL) . J. Biol. Chem. . 272 . 15 . 10248–53 . April 1997 . 9092574 . 10.1074/jbc.272.15.10248 . free .
17. Sattler M, Salgia R, Shrikhande G, Verma S, Uemura N, Law SF, Golemis EA, Griffin JD . Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1) . J. Biol. Chem. . 272 . 22 . 14320–6 . May 1997 . 9162067 . 10.1074/jbc.272.22.14320 . free . 20.500.12613/9173 . free .
18. Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O . Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells . Biochem. Biophys. Res. Commun. . 239 . 2 . 412–7 . October 1997 . 9344843 . 10.1006/bbrc.1997.7480 .
19. Tvorogov D, Carpenter G . EGF-dependent association of phospholipase C-gamma1 with c-Cbl . Exp. Cell Res. . 277 . 1 . 86–94 . July 2002 . 12061819 . 10.1006/excr.2002.5545 .
20. Umebayashi K, Stenmark H, Yoshimori T . Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation . Mol. Biol. Cell . 19 . 8 . 3454–62 . August 2008 . 18508924 . 2488299 . 10.1091/mbc.E07-10-0988 .
21. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A . FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl . Proc. Natl. Acad. Sci. U.S.A. . 99 . 10 . 6684–9 . May 2002 . 11997436 . 124463 . 10.1073/pnas.052138899 . 2002PNAS...99.6684W . free .
22. Deckert M, Elly C, Altman A, Liu YC . Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases . J. Biol. Chem. . 273 . 15 . 8867–74 . April 1998 . 9535867 . 10.1074/jbc.273.15.8867 . free .
23. Jain SK, Langdon WY, Varticovski L . Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase . Oncogene . 14 . 18 . 2217–28 . May 1997 . 9174058 . 10.1038/sj.onc.1201049 . free .
24. Liu SK, McGlade CJ . Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc . Oncogene . 17 . 24 . 3073–82 . December 1998 . 9872323 . 10.1038/sj.onc.1202337 . 6140122 .
25. Ettenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S . cbl-b inhibits epidermal growth factor receptor signaling . Oncogene . 18 . 10 . 1855–66 . March 1999 . 10086340 . 10.1038/sj.onc.1202499 . free .
26. Robertson H, Langdon WY, Thien CB, Bowtell DD . A c-Cbl yeast two hybrid screen reveals interactions with 14-3-3 isoforms and cytoskeletal components . Biochem. Biophys. Res. Commun. . 240 . 1 . 46–50 . November 1997 . 9367879 . 10.1006/bbrc.1997.7608 .
27. Donovan JA, Wange RL, Langdon WY, Samelson LE . The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor . J. Biol. Chem. . 269 . 37 . 22921–4 . September 1994 . 10.1016/S0021-9258(17)31595-8 . 8083187 . free .
28. Saci A, Liu WQ, Vidal M, Garbay C, Rendu F, Bachelot-Loza C . Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement . Biochem. J. . 363 . Pt 3 . 717–25 . May 2002 . 11964172 . 1222524 . 10.1042/0264-6021:3630717 .
29. Odai H, Sasaki K, Iwamatsu A, Nakamoto T, Ueno H, Yamagata T, Mitani K, Yazaki Y, Hirai H . Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl . Blood . 89 . 8 . 2745–56 . April 1997 . 9108392 . 10.1182/blood.V89.8.2745 . free .
30. Howlett CJ, Robbins SM . Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation . Oncogene . 21 . 11 . 1707–16 . March 2002 . 11896602 . 10.1038/sj.onc.1205228 . 34296309 . free .
31. Howlett CJ, Bisson SA, Resek ME, Tigley AW, Robbins SM . The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase . Biochem. Biophys. Res. Commun. . 257 . 1 . 129–38 . April 1999 . 10092522 . 10.1006/bbrc.1999.0427 .
32. Sehat B, Andersson S, Girnita L, Larsson O . Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis . Cancer Res. . 68 . 14 . 5669–77 . July 2008 . 18632619 . 10.1158/0008-5472.CAN-07-6364 .
33. Erdreich-Epstein A, Liu M, Kant AM, Izadi KD, Nolta JA, Durden DL . Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages . J. Leukoc. Biol. . 65 . 4 . 523–34 . April 1999 . 10204582 . 10.1002/jlb.65.4.523 . 18340540 .
34. Park RK, Izadi KD, Deo YM, Durden DL . Role of Src in the modulation of multiple adaptor proteins in FcalphaRI oxidant signaling . Blood . 94 . 6 . 2112–20 . September 1999 . 10477741 . 10.1182/blood.V94.6.2112 .
35. Miyoshi-Akiyama T, Aleman LM, Smith JM, Adler CE, Mayer BJ . Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor . Oncogene . 20 . 30 . 4058–69 . July 2001 . 11494134 . 10.1038/sj.onc.1204528 . free .
36. Bonita DP, Miyake S, Lupher ML, Langdon WY, Band H . 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 . Mol. Cell. Biol. . 17 . 8 . 4597–610 . August 1997 . 9234717 . 232313 . 10.1128/mcb.17.8.4597.
37. Gesbert F, Garbay C, Bertoglio J . 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 . 7 . 3986–93 . February 1998 . 9461587 . 10.1074/jbc.273.7.3986 . free .
38. Zhang S, Broxmeyer HE . p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells . Biochem. Biophys. Res. Commun. . 254 . 2 . 440–5 . January 1999 . 9918857 . 10.1006/bbrc.1998.9959 .
39. Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ . FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival . Bone . 42 . 6 . 1032–9 . June 2008 . 18374639 . 10.1016/j.bone.2008.02.009 .
40. Hartley D, Meisner H, Corvera S . Specific association of the beta isoform of the p85 subunit of phosphatidylinositol-3 kinase with the proto-oncogene c-cbl . J. Biol. Chem. . 270 . 31 . 18260–3 . August 1995 . 7629144 . 10.1074/jbc.270.31.18260 . free .
41. Graham LJ, Stoica BA, Shapiro M, DeBell KE, Rellahan B, Laborda J, Bonvini E . Sequences surrounding the Src-homology 3 domain of phospholipase Cgamma-1 increase the domain's association with Cbl . Biochem. Biophys. Res. Commun. . 249 . 2 . 537–41 . August 1998 . 9712732 . 10.1006/bbrc.1998.9177 .
42. Haglund K, Ivankovic-Dikic I, Shimokawa N, Kruh GD, Dikic I . Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites . J. Cell Sci. . 117 . Pt 12 . 2557–68 . May 2004 . 15128873 . 10.1242/jcs.01148 . 14083271 .
43. Sanjay A, Houghton A, Neff L, DiDomenico E, Bardelay C, Antoine E, Levy J, Gailit J, Bowtell D, Horne WC, Baron R . Cbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility . J. Cell Biol. . 152 . 1 . 181–95 . January 2001 . 11149930 . 2193648 . 10.1083/jcb.152.1.181 .
44. Tanaka Y, Tanaka N, Saeki Y, Tanaka K, Murakami M, Hirano T, Ishii N, Sugamura K . c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130 . Mol. Cell. Biol. . 28 . 15 . 4805–18 . August 2008 . 18519587 . 2493370 . 10.1128/MCB.01784-07 .
45. Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J . Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates . EMBO J. . 27 . 5 . 804–16 . March 2008 . 18273061 . 2265755 . 10.1038/emboj.2008.18 .
46. Wakioka T, Sasaki A, Mitsui K, Yokouchi M, Inoue A, Komiya S, Yoshimura A . APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl . Leukemia . 13 . 5 . 760–7 . May 1999 . 10374881 . 10.1038/sj/leu/2401397 .
47. Watanabe S, Take H, Takeda K, Yu ZX, Iwata N, Kajigaya S . Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes . Biochem. Biophys. Res. Commun. . 278 . 1 . 167–74 . November 2000 . 11071869 . 10.1006/bbrc.2000.3760 .
48. Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I . Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors . Nature . 416 . 6877 . 183–7 . March 2002 . 11894095 . 10.1038/416183a . 2002Natur.416..183S . 635702 .
49. Szymkiewicz I, Kowanetz K, Soubeyran P, Dinarina A, Lipkowitz S, Dikic I . CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases . J. Biol. Chem. . 277 . 42 . 39666–72 . October 2002 . 12177062 . 10.1074/jbc.M205535200 . free .
50. Borinstein SC, Hyatt MA, Sykes VW, Straub RE, Lipkowitz S, Boulter J, Bogler O . SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins . Cell. Signal. . 12 . 11–12 . 769–79 . December 2000 . 11152963 . 10.1016/S0898-6568(00)00129-7 .
51. Park RK, Erdreich-Epstein A, Liu M, Izadi KD, Durden DL . High affinity IgG receptor activation of Src family kinases is required for modulation of the Shc-Grb2-Sos complex and the downstream activation of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase . J. Immunol. . 163 . 11 . 6023–34 . December 1999 . 10.4049/jimmunol.163.11.6023 . 10570290 . 36719981 . free .
52. Pandey A, Ibarrola N, Kratchmarova I, Fernandez MM, Constantinescu SN, Ohara O, Sawasdikosol S, Lodish HF, Mann M . A novel Src homology 2 domain-containing molecule, Src-like adapter protein-2 (SLAP-2), which negatively regulates T cell receptor signaling . J. Biol. Chem. . 277 . 21 . 19131–8 . May 2002 . 11891219 . 10.1074/jbc.M110318200 . free.
53. Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I . The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2 . Biochem. Biophys. Res. Commun. . 300 . 2 . 494–500 . January 2003 . 12504111 . 10.1016/S0006-291X(02)02894-2 .
54. Wong ES, Lim J, Low BC, Chen Q, Guy GR . Evidence for direct interaction between Sprouty and Cbl . J. Biol. Chem. . 276 . 8 . 5866–75 . February 2001 . 11053437 . 10.1074/jbc.M006945200 . free.
55. Lupher ML, Rao N, Lill NL, Andoniou CE, Miyake S, Clark EA, Druker B, Band H . 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 . 52 . 35273–81 . December 1998 . 9857068 . 10.1074/jbc.273.52.35273 . free .
56. Bertagnolo V, Marchisio M, Brugnoli F, Bavelloni A, Boccafogli L, Colamussi ML, Capitani S . Requirement of tyrosine-phosphorylated Vav for morphological differentiation of all-trans-retinoic acid-treated HL-60 cells . Cell Growth Differ. . 12 . 4 . 193–200 . April 2001 . 11331248 .
57. Melander F, Andersson T, Dib K . Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils . Biochem. J. . 370 . Pt 2 . 687–94 . March 2003 . 12435267 . 1223185 . 10.1042/BJ20021201 .
58. Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR . Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling . EMBO J. . 21 . 18 . 4796–808 . September 2002 . 12234920 . 126289 . 10.1093/emboj/cdf493 .
59. Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne WC, Zhang H, Yoshimura A, Baron R . Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7 . J. Biol. Chem. . 274 . 44 . 31707–12 . October 1999 . 10531381 . 10.1074/jbc.274.44.31707 . free .
60. Zheng N, Wang P, Jeffrey PD, Pavletich NP . Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases . Cell . 102 . 4 . 533–9 . August 2000 . 10966114 . 10.1016/S0092-8674(00)00057-X . 14132429 . free .
61. Marengère LE, Mirtsos C, Kozieradzki I, Veillette A, Mak TW, Penninger JM . Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells . J. Immunol. . 159 . 1 . 70–6 . July 1997 . 10.4049/jimmunol.159.1.70 . 9200440 . 33688953 . free .
62. Pedraza-Alva G, Sawasdikosol S, Liu YC, Mérida LB, Cruz-Muñoz ME, Oceguera-Yañez F, Burakoff SJ, Rosenstein Y . Regulation of Cbl molecular interactions by the co-receptor molecule CD43 in human T cells . J. Biol. Chem. . 276 . 1 . 729–37 . January 2001 . 11024037 . 10.1074/jbc.M008494200 . free .
63. Liu YC, Elly C, Yoshida H, Bonnefoy-Berard N, Altman A . Activation-modulated association of 14-3-3 proteins with Cbl in T cells . J. Biol. Chem. . 271 . 24 . 14591–5 . June 1996 . 8663231 . 10.1074/jbc.271.24.14591 . free .
64. Lupher ML, Reedquist KA, Miyake S, Langdon WY, Band H . A novel phosphotyrosine-binding domain in the N-terminal transforming region of Cbl interacts directly and selectively with ZAP-70 in T cells . J. Biol. Chem. . 271 . 39 . 24063–8 . September 1996 . 8798643 . 10.1074/jbc.271.39.24063 . free.
65. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ . Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase . Nature . 398 . 6722 . 84–90 . March 1999 . 10078535 . 10.1038/18050 . 1999Natur.398...84M . 4411124 .