CD44
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CD44抗原為細(xì)胞表面的一種糖蛋白參與了細(xì)胞 - 細(xì)胞相互作用、細(xì)胞黏附和細(xì)胞遷移。在人類中，CD44抗原自第11號(hào)染色體上.[1] 的CD44 基因轉(zhuǎn)錄出。CD44亦被稱為HCAM(homing cell adhesion molecule) (歸巢細(xì)胞黏附分子），PGP-1(phagocytic glycoprotein-1)（吞噬糖蛋白-1），愛(ài)馬仕抗原(Hermes antigen)，淋巴細(xì)胞歸巢受體(lymphocyte homing receptor)，ECM-III和HUTCH-1。
目錄 |
組織分布和異構(gòu)體
CD44表現(xiàn)在大量的哺乳動(dòng)物細(xì)胞。標(biāo)準(zhǔn)異構(gòu)體:CD44s，含有外顯子1-5和16-20會(huì)表現(xiàn)在大多數(shù)細(xì)胞類型。含可變外顯子的CD44剪接變體:CD44V。還有一些上皮細(xì)胞會(huì)表達(dá)結(jié)構(gòu)較大的異構(gòu)體（CD44E），其中包括外顯子V8-10。.[2]
功能
CD44其中一種受體為透明質(zhì)酸(hyaluronic acid)，也可以與其它受質(zhì)，如骨橋蛋白(osteopontin)，膠原蛋白，和基質(zhì)金屬蛋白酶(matrix metalloproteinases，MMPs）進(jìn)行交互作用。而CD44的功能是由其轉(zhuǎn)譯后修飾來(lái)調(diào)控。其中一個(gè)重要的修飾包括對(duì)CD44的獨(dú)立唾液酸化的巖藻糖基化(Sialylated,fucosylated)而這種呈現(xiàn)于CD44的選擇素(selectin)結(jié)合糖型稱為HCELL（為造血細(xì)胞E-selectin/L-selectin配位體）。HCELL糖型最初發(fā)現(xiàn)于人類造血干細(xì)胞和白血病細(xì)胞,[3][4][5][6]，并隨后用于鑒定癌細(xì)胞上.[7][8][9][10][11]。HCELL作為“骨質(zhì)歸巢受體”(bone homing receptor)引導(dǎo)人類造血干細(xì)胞和間葉干細(xì)胞(mesenchymal stem cells)遷移到骨髓.[5]。體外活體細(xì)胞表面聚糖工程已用于強(qiáng)制HCELL的表現(xiàn)于會(huì)表現(xiàn)出的CD44的任何細(xì)胞.[12]。CD44的糖基化也直接控制其對(duì)于纖維蛋白的結(jié)合和纖維蛋白原的固定能力.[13][14]
CD44這種蛋白參與了多種細(xì)胞功能，包括淋巴細(xì)胞的活化、再循環(huán)和歸位(homing)，血細(xì)胞生成和腫瘤轉(zhuǎn)移?；虬l(fā)生復(fù)雜的選擇性剪接會(huì)產(chǎn)生不同種功能不同的亞型;然而，其中一些亞型的性質(zhì)尚未確定。選擇性剪接改變蛋白質(zhì)的結(jié)構(gòu)與功能性，可能與腫瘤轉(zhuǎn)移有關(guān)。利用血液動(dòng)力學(xué)也發(fā)現(xiàn)在直腸癌細(xì)胞中表現(xiàn)出的CD44亞型表面有獨(dú)立唾液酸化的巖藻糖基化(HCELL)的糖型修飾會(huì)與P-, L-, 和E型選擇素還有纖維蛋白進(jìn)行結(jié)合(纖維蛋白原則不會(huì)結(jié)合)，而與選擇素的結(jié)合也意味著腫瘤轉(zhuǎn)移的可能性。CD44轉(zhuǎn)錄的活化部分會(huì)借由β-聯(lián)蛋白以及Wnt信號(hào)傳導(dǎo)進(jìn)行，而這也跟腫瘤發(fā)展有所關(guān)聯(lián)。
臨床意義
該蛋白是一個(gè)決定檢體是否為印度血型(Indian blood group system)的一種因素
- CD44與CD25，用于在胸腺追蹤早期T細(xì)胞的發(fā)展。
- CD44的表達(dá)是一個(gè)指示標(biāo)記效應(yīng)記憶T細(xì)胞(effector-memory T-cells)。記憶細(xì)胞增殖（活化）也可在體外用CFSE(Carboxyfluorescein succinimidyl ester)化學(xué)標(biāo)記進(jìn)行檢測(cè)。
此外，不同的CD44被發(fā)現(xiàn)為可以用于某些乳腺癌(breast cancer)和前列腺癌(prostate cancer)干細(xì)胞的細(xì)胞表面標(biāo)記。在乳腺癌研究CD44 + / CD24-表達(dá)的有無(wú)通常被作為乳房腫瘤干細(xì)胞的確認(rèn)并由此為依據(jù)于將該種乳腺癌細(xì)胞分類成富含干細(xì)胞特性的群體。此種蛋白表現(xiàn)也一直被視為在上皮性卵巢癌(epithelial ovarian cancer)患者提高生存時(shí)間的指標(biāo)。
子宮內(nèi)膜細(xì)胞在子宮內(nèi)膜異位癥(endometriosis demonstrate)會(huì)增加的CD44剪接變異體的表現(xiàn)量，并提高對(duì)腹腔細(xì)胞的附著力。
CD44的變異亞型也與頭頸部鱗狀細(xì)胞癌(ead and neck squamous cell carcinoma)的發(fā)展有關(guān)。
在臨床上會(huì)利用Bivatuzumab(一種人類的單株抗體)來(lái)檢測(cè)CD44 v6(其中一種CD44剪接變異體)
與CD44交互作用的物質(zhì)
CD44會(huì)與下列物質(zhì)進(jìn)行蛋白質(zhì)-蛋白質(zhì)交互作用：
更進(jìn)一步了解
- Sackstein R. Glycosyltransferase-programmed stereosubstitution to create HCELL: Engineering a Roadmap for Cell Migration. Immunological Reviews. July 2009, 230 (1): 51–74. doi:10.1111/j.1600-065X.2009.00792.x. PMID 19594629.
- Sackstein R. The bone marrow is akin to skin: HCELL and the biology of hematopoietic stem cell homing. J. Invest. Dermatol.. May 2004, 122 (5): 1061–9. doi:10.1111/j.0022-202X.2004.09301.x. PMID 15140204.
- Konstantopoulos K, Thomas SN. Cancer cells in transit: the vascular interactions of tumor cells. Annu Rev Biomed Eng. 2009, 11: 177–202. doi:10.1146/annurev-bioeng-061008-124949. PMID 19413512.
- Günthert U. CD44: a multitude of isoforms with diverse functions. Curr. Top. Microbiol. Immunol.. 1994, 184: 47–63. doi:10.1007/978-3-642-78253-4_4. PMID 7508842.
- Yasuda M, Nakano K, Yasumoto K, Tanaka Y. CD44: functional relevance to inflammation and malignancy. Histol. Histopathol.. 2003, 17 (3): 945–50. PMID 12168806.
- Sun CX, Robb VA, Gutmann DH. Protein 4.1 tumor suppressors: getting a FERM grip on growth regulation. J. Cell. Sci.. 2003, 115 (Pt 21): 3991–4000. doi:10.1242/jcs.00094. PMID 12356905.
- Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nature Reviews Molecular Cell Biology. 2003, 4 (1): 33–45. doi:10.1038/nrm1004. PMID 12511867.
- Martin TA, Harrison G, Mansel RE, Jiang WG. The role of the CD44/ezrin complex in cancer metastasis. Crit. Rev. Oncol. Hematol.. 2004, 46 (2): 165–86. doi:10.1016/S1040-8428(02)00172-5. PMID 12711360.
參考文獻(xiàn)
- ↑ Spring FA, Dalchau R, Daniels GL, Mallinson G, Judson PA, Parsons SF, Fabre JW, Anstee DJ. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC1385183/ The Ina and Inb blood group antigens are located on a glycoprotein of 80,000 MW (the CDw44 glycoprotein) whose expression is influenced by the In(Lu) gene]. Immunology. May 1988, 64 (1): 37–43. PMID 2454887. PMC 1385183.
- ↑ Goodison S, Urquidi V, Tarin D. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC395698/ CD44 cell adhesion molecules]. MP, Mol. Pathol.. August 1999, 52 (4): 189–96. doi:10.1136/mp.52.4.189. PMID 10694938. PMC 395698.
- ↑ Oxley SM, Sackstein R. Detection of an L-selectin ligand on a hematopoietic progenitor cell line. Blood. November 1994, 84 (10): 3299–306. PMID 7524735.
- ↑ Sackstein R, Dimitroff CJ. A hematopoietic cell L-selectin ligand that is distinct from PSGL-1 and displays N-glycan-dependent binding activity. Blood. October 2000, 96 (8): 2765–74. PMID 11023510.
- ↑ 5.0 5.1 Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP, Wohlgemuth R. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat. Med.. February 2008, 14 (2): 181–7. doi:10.1038/nm1703. PMID 18193058.
- ↑ Dimitroff CJ, Lee JY, Rafii S, Fuhlbrigge RC, Sackstein R. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2192031/ Cd44 Is a Major E-Selectin Ligand on Human Hematopoietic Progenitor Cells]. J. Cell Biol.. June 2001, 153 (6): 1277–86. doi:10.1083/jcb.153.6.1277. PMID 11402070. PMC 2192031.
- ↑ Hanley WD, Burdick MM, Konstantopoulos K, Sackstein R. CD44 on LS174T colon carcinoma cells possesses E-selectin ligand activity. Cancer Res.. July 2005, 65 (13): 5812–7. doi:10.1158/0008-5472.CAN-04-4557. PMID 15994957.
- ↑ Burdick MM, Chu JT, Godar S, Sackstein R. HCELL is the major E- and L-selectin ligand expressed on LS174T colon carcinoma cells. J. Biol. Chem.. May 2006, 281 (20): 13899–905. doi:10.1074/jbc.M513617200. PMID 16565092.
- ↑ 9.0 9.1 Hanley WD, Napier SL, Burdick MM, Schnaar RL, Sackstein R, Konstantopoulos K.. Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells. FASEB J. Dec 2005, 20 (2): 337–9. doi:10.1096/fj.05-4574fje. PMID 16352650.
- ↑ 10.0 10.1 Napier SL, Healy ZR, Schnaar RL, Konstantopoulos K. Selectin ligand expression regulates the initial vascular interactions of colon carcinoma cells: the roles of CD44v and alternative sialofucosylated selectin ligands. J Biol Chem. Feb 2007, 282 (6): 3433–41. doi:10.1074/jbc.M607219200. PMID 17135256.
- ↑ 11.0 11.1 Thomas SN, Zhu F, Schnaar RL, Alves CS, Konstantopoulos K. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2414264/ Carcinoembryonic Antigen and CD44 Variant Isoforms Cooperate to Mediate Colon Carcinoma Cell Adhesion to E- and L-selectin in Shear Flow]. J Biol Chem. Jun 2008, 283 (23): 15647–55. doi:10.1074/jbc.M800543200. PMID 18375392. PMC 2414264.
- ↑ Sackstein R. Glycosyltransferase-programmed stereosubstitution (GPS) to create HCELL: engineering a roadmap for cell migration. Immunol. Rev.. July 2009, 230 (1): 51–74. doi:10.1111/j.1600-065X.2009.00792.x. PMID 19594629.
- ↑ 13.0 13.1 Alves CS, Burdick MM, Thomas SN, Pawar P, Konstantopoulos K. The dual role of CD44 as a functional P-selectin ligand and fibrin receptor in colon carcinoma cell adhesion. Am J Physiol Cell Physiol. Apr 2008, 294 (4): C907–16. doi:10.1152/ajpcell.00463.2007. PMID 18234849.
- ↑ 14.0 14.1 Alves CS, Yakovlev S, Medved L, Konstantopoulos K. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2613610/ Biomolecular Characterization of CD44-Fibrin(ogen) Binding: DISTINCT MOLECULAR REQUIREMENTS MEDIATE BINDING OF STANDARD AND VARIANT ISOFORMS OF CD44 TO IMMOBILIZED FIBRIN(OGEN)]. J Biol Chem. Jan 2009, 284 (2): 1177–89. doi:10.1074/jbc.M805144200. PMID 19004834. PMC 2613610.
- ↑ Bourguignon LY, Singleton PA, Zhu H, Diedrich F. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J. Biol. Chem.. August 2003, 278 (32): 29420–34. doi:10.1074/jbc.M301885200. PMID 12748184.
- ↑ Zohar R, Suzuki N, Suzuki K, Arora P, Glogauer M, McCulloch CA, Sodek J. Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration. J Cell Physiol. July 2000, 184 (1): 118–130. doi:10.1002/(SICI)1097-4652(200007)184:1<118::AID-JCP13>3.0.CO;2-Y. PMID 10825241.
- ↑ Jalkanen S, Jalkanen M. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC2289325/ Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin]. J. Cell Biol.. February 1992, 116 (3): 817–25. doi:10.1083/jcb.116.3.817. PMID 1730778. PMC 2289325.
- ↑ 18.0 18.1 Ilangumaran S, Briol A, Hoessli DC. CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes. Blood. May 1998, 91 (10): 3901–8. PMID 9573028.
- ↑ Taher TE, Smit L, Griffioen AW, Schilder-Tol EJ, Borst J, Pals ST. Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes. J. Biol. Chem.. February 1996, 271 (5): 2863–7. doi:10.1074/jbc.271.5.2863. PMID 8576267.
- ↑ Bourguignon LY, Zhu H, Shao L, Chen YW. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J. Biol. Chem.. March 2001, 276 (10): 7327–36. doi:10.1074/jbc.M006498200. PMID 11084024.
- Sackstein, Robert. [http//www.ncbi.nlm.nih.gov/pmc/articles/PMC3145154/ The Biology of CD44 and HCELL in Hematopoiesis: The "Step 2-bypass Pathway" and other Emerging Perspectives]. Current Opinion in Hematology. July 2011, 18 (4): 239–248. doi:10.1097/MOH.0b013e3283476140. PMID 21546828. PMC 3145154.
外部鏈接
- Indian blood group system at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH
- Articles at IHOP.
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