CBL (遺伝子)
Cbl(Casitas B-lineage Lymphoma)は、細胞シグナリングとタンパク質のユビキチン化に関与するE3ユビキチンリガーゼ、CBLタンパク質をコードする遺伝子である。この遺伝子の変異は、ヒトの多くの種類のがん、特に急性骨髄性白血病と関係している[5]。
発見
[編集]1989年に発見されたウイルスにコードされたマウスCbl遺伝子の断片が、Cblファミリーの最初のメンバーである[6]。その断片は、正常なマウスのCbl(c-Cbl)と区別するためにv-Cblと名付けられた。実験で用いられたウイルスは、カリフォルニア州・カシータス湖で捕獲されたマウスの脳から単離されたマウス白血病ウイルスのマウス指向性株(Cas-Br-M)であり[7]、注入されたマウスからc-Cbl遺伝子の約1/3を切り出していることが判明した。シーケンシングによって、レトロウイルスが保持している断片はチロシンキナーゼ結合ドメインをコードしていることが明らかとなった。この断片に発がん性があり、全長のc-Cblを保持しているレトロウイルスは腫瘍形成を誘導しなかった。形質転換されたレトロウイルスは、感染したマウスに対しCasitas B-lineage lymphomaとして知られるpre-B細胞リンパ腫の一種を常に誘導することが判明した。
構造
[編集]全長のc-Cblは、機能的に異なるドメインをコードする複数の領域から構成されている。
- N末端のチロシンキナーゼ結合ドメイン(TKBドメイン): タンパク質の結合相手を決定する
- RINGフィンガードメイン: ユビキチン化に関与する酵素をリクルートする
- プロリンリッチ領域: CblとCblのアダプター機能に関与する細胞質タンパク質との相互作用部位
- C末端のユビキチン結合ドメイン(UBAドメイン): ユビキチンの結合部位
このドメイン構造とタンパク質産物のチロシンとセリンに富む構成は、細胞シグナリング経路で利用される「アダプター分子」に典型的なものである[8]。
ホモログ
[編集]哺乳類では3つのホモログが同定されており、それらはC末端のUBAドメインの長さが異なるためにアダプタータンパク質としての機能が異なる。
- c-Cbl: 普遍的に発現、ヒトでは906アミノ酸、マウスでは913アミノ酸。
- Cbl-b: 普遍的に発現、982アミノ酸。
- Cbl-c: UBAドメインが欠失しており、474アミノ酸。主に上皮細胞で発現しているが、その機能は未解明。
c-CblとCbl-bにはキイロショウジョウバエ Drosophila melanogaster(D-Cbl)と線虫 Caenorhabditis elegans(Sli-1)にオルソログが存在し、これらのタンパク質の長い進化的経路が示唆される[8]。
機能
[編集]ユビキチンリガーゼ
[編集]ユビキチン化とはタンパク質にユビキチンを化学的に結合させる過程であり、それに伴ってタンパク質は分解の標的となる。この過程は複数段階からなり、いくつかの酵素が関与している。最後に関与するのがE3ファミリーのリガーゼである。CblはE3リガーゼとして機能し、ユビキチンとCblのタンパク質基質(典型的には受容体型チロシンキナーゼ)の間の共有結合の形成を触媒する。RINGフィンガードメインはこの転移を媒介するが、他のRING型E3リガーゼと同様、ユビキチンとRINGフィンガードメインとの間に中間体となる共有結合は形成されない。基質となる受容体型チロシンキナーゼへのユビキチンの結合によって、受容体型チロシンキナーゼは細胞膜から除去され、その後の分解のためにリソソームへ輸送される。
相互作用
[編集]Cblは次に挙げる因子と相互作用することが示されている。
- ABL[9][10]
- ARHGEF7[11]
- C-Met[12][13]
- CD2AP[14][15][16]
- CSF1R[17]
- CRK[18][19]
- CRKL[20][21][22][23][24][25][26][27]
- EGFR[12][28][29]
- FRS2[30]
- FYN[24][31]
- GRB2[12][18][19][20][30][32][33][34][35][36][37][38][39]
- HCK[40][41]
- IGF1R[42]
- LCP2[20][43]
- NCK1[9][20]
- PDGFRA[44]
- PIK3R1[18][45][46]
- PIK3R2[21][47]
- PLCG1[28][48]
- PTK2B[14][49]
- PTPN11[50]
- SH2B2[12][51]
- SH3KBP1[13][52][53][54][55]
- SHC1[18][32]
- SLA2[56]
- SORBS1[14][57]
- SORBS2[10][14]
- SPRY2[12][58][59]
- Syk[60][61][62]
- UBE2L3[58][63][64]
- VAV1[61][65]
- YWHAB[36]
- YWHAQ[66][67]
- ZAP70[68][69]
出典
[編集]- ^ a b c GRCh38: Ensembl release 89: ENSG00000110395 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034342 - Ensembl, May 2017
- ^ Human PubMed Reference:
- ^ Mouse PubMed Reference:
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- ^ a 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). doi:10.1038/sj.onc.1201074. PMID 9178909.
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- ^ a b “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). doi:10.1093/intimm/13.1.13. PMID 11133830.
- ^ “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). PMID 9820532.
- ^ “CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling”. J. Immunol. 160 (10): 5018–27. (May 1998). PMID 9590251.
- ^ a b “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). doi:10.4049/jimmunol.169.7.3793. PMID 12244174.
- ^ “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). doi:10.1074/jbc.272.15.10248. PMID 9092574.
- ^ “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). doi:10.1074/jbc.272.22.14320. PMID 9162067.
- ^ “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). doi:10.1006/bbrc.1997.7480. PMID 9344843.
- ^ a b “EGF-dependent association of phospholipase C-gamma1 with c-Cbl”. Exp. Cell Res. 277 (1): 86–94. (July 2002). doi:10.1006/excr.2002.5545. PMID 12061819.
- ^ “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). doi:10.1091/mbc.E07-10-0988. PMC 2488299. PMID 18508924 .
- ^ a b “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). doi:10.1073/pnas.052138899. PMC 124463. PMID 11997436 .
- ^ “Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases”. J. Biol. Chem. 273 (15): 8867–74. (April 1998). doi:10.1074/jbc.273.15.8867. PMID 9535867.
- ^ a b “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). PMID 10570290.
- ^ “Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase”. Oncogene 14 (18): 2217–28. (May 1997). doi:10.1038/sj.onc.1201049. PMID 9174058.
- ^ “Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc”. Oncogene 17 (24): 3073–82. (December 1998). doi:10.1038/sj.onc.1202337. PMID 9872323.
- ^ “cbl-b inhibits epidermal growth factor receptor signaling”. Oncogene 18 (10): 1855–66. (March 1999). doi:10.1038/sj.onc.1202499. PMID 10086340.
- ^ a b “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). doi:10.1006/bbrc.1997.7608. PMID 9367879.
- ^ “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). PMID 8083187.
- ^ “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). doi:10.1042/0264-6021:3630717. PMC 1222524. PMID 11964172 .
- ^ “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). PMID 9108392.
- ^ “Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation”. Oncogene 21 (11): 1707–16. (March 2002). doi:10.1038/sj.onc.1205228. PMID 11896602.
- ^ “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). doi:10.1006/bbrc.1999.0427. PMID 10092522.
- ^ “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). doi:10.1158/0008-5472.CAN-07-6364. PMID 18632619.
- ^ “Role of Src in the modulation of multiple adaptor proteins in FcalphaRI oxidant signaling”. Blood 94 (6): 2112–20. (September 1999). PMID 10477741.
- ^ “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). doi:10.1128/mcb.17.8.4597. PMC 232313. PMID 9234717 .
- ^ “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). doi:10.1006/bbrc.1998.9959. PMID 9918857.
- ^ “FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival”. Bone 42 (6): 1032–9. (June 2008). doi:10.1016/j.bone.2008.02.009. PMID 18374639.
- ^ “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). doi:10.1074/jbc.270.31.18260. PMID 7629144.
- ^ “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). doi:10.1006/bbrc.1998.9177. PMID 9712732.
- ^ “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). doi:10.1083/jcb.152.1.181. PMC 2193648. PMID 11149930 .
- ^ “c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130”. Mol. Cell. Biol. 28 (15): 4805–18. (August 2008). doi:10.1128/MCB.01784-07. PMC 2493370. PMID 18519587 .
- ^ “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). doi:10.1038/sj/leu/2401397. PMID 10374881.
- ^ “Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes”. Biochem. Biophys. Res. Commun. 278 (1): 167–74. (November 2000). doi:10.1006/bbrc.2000.3760. PMID 11071869 .
- ^ “Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors”. Nature 416 (6877): 183–7. (March 2002). doi:10.1038/416183a. PMID 11894095.
- ^ “CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases”. J. Biol. Chem. 277 (42): 39666–72. (October 2002). doi:10.1074/jbc.M205535200. PMID 12177062.
- ^ “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). doi:10.1016/S0898-6568(00)00129-7. PMID 11152963.
- ^ “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). doi:10.1074/jbc.M110318200. PMID 11891219.
- ^ “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). doi:10.1016/S0006-291X(02)02894-2. PMID 12504111.
- ^ a b “Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling”. EMBO J. 21 (18): 4796–808. (September 2002). doi:10.1093/emboj/cdf493. PMC 126289. PMID 12234920 .
- ^ “Evidence for direct interaction between Sprouty and Cbl”. J. Biol. Chem. 276 (8): 5866–75. (February 2001). doi:10.1074/jbc.M006945200. PMID 11053437.
- ^ “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). doi:10.1074/jbc.273.52.35273. PMID 9857068.
- ^ a b “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). PMID 11331248.
- ^ “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). doi:10.1042/BJ20021201. PMC 1223185. PMID 12435267 .
- ^ “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). doi:10.1074/jbc.274.44.31707. PMID 10531381.
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- ^ “Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells”. J. Immunol. 159 (1): 70–6. (July 1997). PMID 9200440.
- ^ “Regulation of Cbl molecular interactions by the co-receptor molecule CD43 in human T cells”. J. Biol. Chem. 276 (1): 729–37. (January 2001). doi:10.1074/jbc.M008494200. PMID 11024037.
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関連文献
[編集]- “The Cbl family of signal transduction molecules”. Crit Rev Oncog 8 (4): 359–79. (1997). doi:10.1615/critrevoncog.v8.i4.50. PMID 9622055.
- “The c-Cbl oncoprotein”. Int. J. Biochem. Cell Biol. 30 (4): 439–44. (1998). doi:10.1016/S1357-2725(97)00075-7. PMID 9675877.
- “Regulation of immune responses by E3 ubiquitin-protein ligases”. Curr. Dir. Autoimmun.. Current Directions in Autoimmunity 5: 161–75. (2002). doi:10.1159/000060552. ISBN 3-8055-7308-1. PMID 11826757.
外部リンク
[編集]- Quips article describing CBL function at PDBe
- OMIM enteries on NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA and CBL
- Human CBL genome location and CBL gene details page in the UCSC Genome Browser.