CD44
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CD44抗原為細胞表面的一種糖蛋白參與了細胞 - 細胞相互作用、細胞黏附和細胞遷移。在人類中，CD44抗原自第11號染色體上.[1] 的CD44 基因轉錄出。CD44亦被稱為HCAM(homing cell adhesion molecule) (歸巢細胞黏附分子），PGP-1(phagocytic glycoprotein-1)（吞噬糖蛋白-1），愛馬仕抗原(Hermes antigen)，淋巴細胞歸巢受體(lymphocyte homing receptor)，ECM-III和HUTCH-1。
目錄 |
組織分布和異構體
CD44表現在大量的哺乳動物細胞。標準異構體:CD44s，含有外顯子1-5和16-20會表現在大多數細胞類型。含可變外顯子的CD44剪接變體:CD44V。還有一些上皮細胞會表達結構較大的異構體（CD44E），其中包括外顯子V8-10。.[2]
功能
CD44其中一種受體為透明質酸(hyaluronic acid)，也可以與其它受質，如骨橋蛋白(osteopontin)，膠原蛋白，和基質金屬蛋白酶(matrix metalloproteinases，MMPs）進行交互作用。而CD44的功能是由其轉譯後修飾來調控。其中一個重要的修飾包括對CD44的獨立唾液酸化的岩藻糖基化(Sialylated,fucosylated)而這種呈現於CD44的選擇素(selectin)結合糖型稱為HCELL（為造血細胞E-selectin/L-selectin配位體）。HCELL糖型最初發現於人類造血幹細胞和白血病細胞,[3][4][5][6]，並隨後用於鑒定癌細胞上.[7][8][9][10][11]。HCELL作為「骨質歸巢受體」(bone homing receptor)引導人類造血幹細胞和間葉幹細胞(mesenchymal stem cells)遷移到骨髓.[5]。體外活體細胞表面聚糖工程已用於強制HCELL的表現於會表現出的CD44的任何細胞.[12]。CD44的糖基化也直接控制其對於纖維蛋白的結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胞功能，包括淋巴細胞的活化、再循環和歸位(homing)，血細胞生成和腫瘤轉移。基因發生複雜的選擇性剪接會產生不同種功能不同的亞型;然而，其中一些亞型的性質尚未確定。選擇性剪接改變蛋白質的結構與功能性，可能與腫瘤轉移有關。利用血液動力學也發現在直腸癌細胞中表現出的CD44亞型表面有獨立唾液酸化的岩藻糖基化(HCELL)的糖型修飾會與P-, L-, 和E型選擇素還有纖維蛋白進行結合(纖維蛋白原則不會結合)，而與選擇素的結合也意味著腫瘤轉移的可能性。CD44轉錄的活化部分會藉由β-聯蛋白以及Wnt信號傳導進行，而這也跟腫瘤發展有所關聯。
臨床意義
該蛋白是一個決定檢體是否為印度血型(Indian blood group system)的一種因素
- CD44與CD25，用於在胸腺追蹤早期T細胞的發展。
- CD44的表達是一個指示標記效應記憶T細胞(effector-memory T-cells)。記憶細胞增殖（活化）也可在體外用CFSE(Carboxyfluorescein succinimidyl ester)化學標記進行檢測。
此外，不同的CD44被發現為可以用於某些乳腺癌(breast cancer)和前列腺癌(prostate cancer)幹細胞的細胞表面標記。在乳腺癌研究CD44 + / CD24-表達的有無通常被作為乳房腫瘤幹細胞的確認並由此為依據於將該種乳腺癌細胞分類成富含幹細胞特性的群體。此種蛋白表現也一直被視為在上皮性卵巢癌(epithelial ovarian cancer)患者提高生存時間的指標。
子宮內膜細胞在子宮內膜異位症(endometriosis demonstrate)會增加的CD44剪接變異體的表現量，並提高對腹腔細胞的附著力。
CD44的變異亞型也與頭頸部鱗狀細胞癌(ead and neck squamous cell carcinoma)的發展有關。
在臨床上會利用Bivatuzumab(一種人類的單株抗體)來檢測CD44 v6(其中一種CD44剪接變異體)
與CD44交互作用的物質
CD44會與下列物質進行蛋白質-蛋白質交互作用：
更進一步了解
- 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
- ↑ 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.
外部連結
- Indian blood group system at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH
- Articles at IHOP.
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