STRUCTURE

CD10 is a type 2 transmembrane glycoprotein of M13 family.^1-2 It displays a short cytoplasmatic N-terminal domain involved in signaling.¹ The long extracellular C-terminal domain has catalytic activity and contains a zincin motif.^{1, 3-4}

1. Shipp MA, Richardson NE, Sayre PH, Brown NR, Masteller EL, Clayton LK, Ritz J, Reinherz EL. Molecular cloning of the common acute lymphoblastic leukemia antigen (CALLA) identifies a type II integral membrane protein. Proc Natl Acad Sci U S A. 1988;85:4819-23.
2. Erdös EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J. 1989;3:145-51.
3. Shipp MA, Look AT. Hematopoietic differentiation antigens that are membrane-associated enzymes: cutting is the key! Blood. 1993:15;82:1052-70.
4. Tam LT, Engelbrecht S, Talent JM, Gracy RW, Erdös EG. The importance of disulfide bridges in human endopeptidase (enkephalinase) after proteolytic cleavage. Biochem Biophys Res Commun. 1985;133:1187-92

LIGANDS

Extracellular
Biologically active peptides including enkephalins^1-2, fMLP³, neurotensin⁴, substance P^4-5, amyloid β-peptide⁶, bradykinin^1,3, angiotensin I and II¹, oxytocin⁷, endothelins⁸, calcitonin gene-related peptide⁵, FGF-2⁹, IL1 beta¹⁰, atrial natriuretic factor¹¹ and bombesin-like peptides. ¹²

Intracellular associate molecules

Lyn¹³, PTEN¹⁴ and ERM proteins.¹⁵

1. Gafford JT, Skidgel RA, Erdös EG, Hersh LB. Human kidney "enkephalinase", a neutral metalloendopeptidase that cleaves active peptides. Biochemistry. 1983;22:3265-71.
2. Malfroy B, Swerts JP, Guyon A, Roques BP, Schwartz JC. High-affinity enkephalin-degrading peptidase in brain is increased after morphine. Nature. 1978;276:523-6.
3. Connelly JC, Skidgel RA, Schulz WW, Johnson AR, Erdös EG. Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide. ProcNatl Acad Sci U S A. 1985;82:8737-41.
4. Skidgel RA, Engelbrecht S, Johnson AR, Erdös EG. Hydrolysis of substance p and neurotensin by converting enzyme and neutral endopeptidase. Peptides. 1984;5:769-76.
5. Katayama M, Nadel JA, Bunnett NW, Di Maria GU, Haxhiu M, Borson DB. Catabolism of calcitonin gene-related peptide and substance P by neutral endopeptidase. Peptides. 1991;12:563-7.
6. Shirotani K, Tsubuki S, Iwata N, Takaki Y, Harigaya W, Maruyama K, Kiryu-Seo S, Kiyama H, Iwata H, Tomita T, Iwatsubo T, Saido TC. Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem. 2001;276:21895-901.
7. Johnson AR, Skidgel RA, Gafford JT, Erdös EG. Enzymes in placental microvilli: angiotensin I converting enzyme, angiotensinase A, carboxypeptidase, and neutral endopeptidase ("enkephalinase"). Peptides. 1984;5:789-96.
8. Vijayaraghavan J, Scicli AG, Carretero OA, Slaughter C, Moomaw C, Hersh LB. The hydrolysis of endothelins by neutral endopeptidase 24.11 enkephalinase. J Biol Chem. 1990;265:14150-5.
9. Horiguchi A, Chen DY, Goodman OB Jr, Zheng R, Shen R, Guan H, Hersh LB, Nanus DM. Neutral endopeptidase inhibits prostate cancer tumorigenesis by reducing FGF-2-mediated angiogenesis. Prostate Cancer Prostatic Dis. 2008;11:79-87.
10. Delikat SE, Galvani DW, Zuzel M. A function of CD10 on bone marrow stroma. Br J Haematol. 1994;87:655-7.
11. Kenny AJ, Stephenson SL. Role of endopeptidase-24.11 in the inactivation of atrial natriuretic peptide. FEBS Lett. 1988;9;232:1-8.
12. Shipp MA, Tarr GE, Chen CY, Switzer SN, Hersh LB, Stein H, Sunday ME, Reinherz EL. CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc Natl Acad Sci U S A. 1991;88:10662-6.
13. Ganju RK, Shpektor RG, Brenner DG, Shipp MA. CD10/neutral endopeptidase 24.11 is phosphorylated by casein kinase II and coassociates with other phosphoproteins including the lyn src-related kinase. Blood. 1996;88:4159-65.
14. Sumitomo M, Iwase A, Zheng R, Navarro D, Kaminetzky D, Shen R, Georgescu MM,Nanus DM. Synergy in tumor suppression by direct interaction of neutralendopeptidase with PTEN. Cancer Cell. 2004;5:67-78.
15. Iwase A, Shen R, Navarro D, Nanus DM. Direct binding of neutral endopeptidase 24.11 to ezrin/radixin/moesin (ERM) proteins competes with the interaction ofCD44 with ERM proteins. J Biol Chem. 2004;279:11898-905.

CD10 is expressed transiently on different stages of B-cell maturation. CD10 is displayed on common lymphoid progenitors, pro-B cells, pre-B cells I and II, immature B cells and transitional B cells but not in mature B cells.^1-3 Expression of CD10 is recovered on follicular center B cells.⁴

It is also expressed on neutrophils⁵, fibroblasts⁶, endometrial stromal cells⁷, renal tubular and glomerular cells⁸, myoepithelial cells of adult breast⁸, epithelial cells of prostate⁹, colon¹⁰, stomach¹⁰ and fetal small intestine⁸, immature lymphoid cells¹¹, fetal thymocytes¹¹, canaliculi surface of hepatocytes^12, astrocytes¹³, neuronal cells¹⁴, bone marrow-derived mesenchymal stem cells¹⁵, adipose-derived stem cell¹⁶, mammary stem cells¹⁷, granulocytes¹⁸, apoptotic T cells¹⁹ and follicular helper T cells. ²⁰

It is lowly present on endothelial cells⁶ and prostate stromal cells. ⁹

1. Blom B, Spits H. Development of human lymphoid cells. Annu Rev Immunol. 2006;24:287-320.
2. Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105:4390-8.
3. Hystad ME, Myklebust JH, Bø TH, Sivertsen EA, Rian E, Forfang L, Munthe E, Rosenwald A, Chiorazzi M, Jonassen I, Staudt LM, Smeland EB. Characterization of early stages of human B cell development by gene expression profiling. J Immunol. 2007;179:3662-71.
4. Dogan A, Bagdi E, Munson P, Isaacson PG. CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue addddnd B-cell lymphomas. Am J Surg Pathol. 2000;24:846-52.
5. Painter RG, Dukes R, Sullivan J, Carter R, Erdös EG, Johnson AR. Function of neutral endopeptidase on the cell membrane of human neutrophils. J Biol Chem. 1988;263:9456-61.
6. Johnson AR, Ashton J, Schulz WW, Erdös EG. Neutral metalloendopeptidase in human lung tissue and cultured cells. Am Rev Respir Dis. 1985;132:564-8.
7. Imai K, Kanzaki H, Fujiwara H, Kariya M, Okamoto N, Takakura K, Maeda M, Mori T. Expression of aminopeptidase N and neutral endopeptidase on the endometrial stromal cells in endometriosis and adenomyosis. Hum Reprod. 1992;7:1326-8.
8. Metzgar RS, Borowitz MJ, Jones NH, Dowell BL. Distribution of common acute lymphoblastic leukemia antigen in nonhematopoietic tissues. J Exp Med. 1981;154:1249-54.
9. Song J, Aumüller G, Xiao F, Wilhelm B, Albrecht M. Cell specific expression of CD10/neutral endopeptidase 24.11 gene in human prostatic tissue and cells. Prostate. 2004;58:394-405.
10. Sato Y, Itoh F, Hinoda Y, Ohe Y, Nakagawa N, Ueda R, Yachi A, Imai K. Expression of CD10/neutral endopeptidase in normal and malignant tissues of the human stomach and colon. J Gastroenterol. 1996;31:12-7.
11. Greaves MF, Hariri G, Newman RA, Sutherland DR, Ritter MA, Ritz J. Selective expression of the common acute lymphoblastic leukemia (gp 100) antigen on immature lymphoid cells and their malignant counterparts. Blood. 1983;61:628-39.
12. Loke SL, Leung CY, Chiu KY, Yau WL, Cheung KN, Ma L. Localisation of CD10 to biliary canaliculi by immunoelectron microscopical examination. J Clin Pathol. 1990;43:654-6.
13. Mulder SD, Veerhuis R, Blankenstein MA, Nielsen HM. The effect of amyloid associated proteins on the expression of genes involved in amyloid-β clearance by adult human astrocytes. Exp Neurol. 2012;233:373-9.
14. Wang R, Wang S, Malter JS, Wang DS. Effects of HNE-modification induced by Abeta on neprilysin expression and activity in SH-SY5Y cells. J Neurochem. 2009;108:1072-82.
15. Siegel G, Kluba T, Hermanutz-Klein U, Bieback K, Northoff H, Schäfer R. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 2013;11:146.
16. Raposio E, Bonomini S, Calderazzi F. Isolation of autologous adipose tissue-derived mesenchymal stem cells for bone repair. Orthop Traumatol Surg Res. 2016;102:909-912.
17. Bachelard-Cascales E, Chapellier M, Delay E, Pochon G, Voeltzel T, Puisieux A,Caron de Fromentel C, Maguer-Satta V. The CD10 enzyme is a key player to identify and regulate human mammary stem cells. Stem Cells. 2010;28:1081-8.
18. Braun MP, Martin PJ, Ledbetter JA, Hansen JA. Granulocytes and cultured human fibroblasts express common acute lymphoblastic leukemia-associated antigens. Blood. 1983;61:718-25.
19. Cutrona G, Leanza N, Ulivi M, Melioli G, Burgio VL, Mazzarello G, Gabutti ,Roncella S, Ferrarini M. Expression of CD10 by human T cells that undergo apoptosis both in vitro and in vivo. Blood. 1999;94:3067-76.
20. Amé-Thomas P, Hoeller S, Artchounin C, Misiak J, Braza MS, Jean R, Le Priol J, Monvoisin C, Martin N, Gaulard P, Tarte K. CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells. Blood. 2015;125:2381-5.

CD10 is a zinc-dependent metalloendoprotease which cleaves several biologically active peptides.¹ It regulates inflammation through degradation of proinflammatory molecules.² CD10 is also involved in metabolizing amyloid B-peptides in the brain and regulates the maturation of B cells in mice.^3-4 CD10 processes several neuropeptides including enkephalins and substance P.^5-6 Last, CD10 modulates both lung and breast morphogenesis.^7-8

1. Maguer-Satta V, Besançon R, Bachelard-Cascales E. Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer. Stem Cells. 2011;29:389-96.
2. Shipp MA, Stefano GB, Switzer SN, Griffin JD, Reinherz EL. CD10 (CALLA)/neutral endopeptidase 24.11 modulates inflammatory peptide-induced changes in neutrophil morphology, migration, and adhesion proteins and is itself regulated by neutrophil activation. Blood. 1991;78:1834-41.
3. Shirotani K, Tsubuki S, Iwata N, Takaki Y, Harigaya W, Maruyama K, Kiryu-Seo S, Kiyama H, Iwata H, Tomita T, Iwatsubo T, Saido TC. Neprilysin degrades both amyloid beta peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem. 2001;276:21895-901.
4. Salles G, Rodewald HR, Chin BS, Reinherz EL, Shipp MA. Inhibition ofCD10/neutral endopeptidase 24.11 promotes B-cell reconstitution and maturation in vivo. Proc Natl Acad Sci U S A. 1993;90:7618-22.
5. Vijayaraghavan J, Scicli AG, Carretero OA, Slaughter C, Moomaw C, Hersh LB. The hydrolysis of endothelins by neutral endopeptidase 24.11 enkephalinase). J Biol Chem. 1990;265:14150-5.
6. Skidgel RA, Engelbrecht S, Johnson AR, Erdös EG. Hydrolysis of substance p and neurotensin by converting enzyme and neutral endopeptidase. Peptides. 1984;5:769-76.
7. Sunday ME, Hua J, Torday JS, Reyes B, Shipp MA. CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation. J Clin Invest. 1992;90:2517-25.
8. Atherton AJ, Anbazhagan R, Monaghan P, Bartek J, Gusterson BA. Immunolocalisation of cell surface peptidases in the developing human breast. Differentiation. 1994;56:101-6.

Cell marker

Can be used for the identification of the stage of B cells¹ and for classification of B cell leukemias and lymphomas.² CD10 is also a marker of renal and hepatic neoplasias^3-4, endometrial and thyroid neoplasms.^5-6

Useful as a prognostic marker in cancer including breast carcinoma⁷, ovarian cancer⁸, head and neck squamous carcinoma⁹, prostate cancer¹⁰,acute lymphoblastic leukemia¹¹ and renal malignancies.⁴

1. Vale AM, Schroeder HW Jr. Clinical consequences of defects in B-cell development. J Allergy Clin Immunol. 2010;125:778-87.
2. Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008;111:3941-67.
3. Borscheri N, Roessner A, Röcken C. Canalicular immunostaining of neprilysin (CD10) as a diagnostic marker for hepatocellular carcinomas. Am J Surg Pathol. 2001;25:1297-303.
4. Langner C, Ratschek M, Rehak P, Schips L, Zigeuner R. CD10 is a diagnostic and prognostic marker in renal malignancies. Histopathology. 2004;45:460-7.
5. Tomoda C, Kushima R, Takeuti E, Mukaisho K, Hattori T, Kitano H. CD10 expression is useful in the diagnosis of follicular carcinoma and follicular variant of papillary thyroid carcinoma. Thyroid. 2003;13:291-5.
6. McCluggage WG, Sumathi VP, Maxwell P. CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. Histopathology. 2001;39:273-8.
7. Makretsov NA, Hayes M, Carter BA, Dabiri S, Gilks CB, Huntsman DG. Stromal CD10 expression in invasive breast carcinoma correlates with poor prognosis, estrogen receptor negativity, and high grade. Mod Pathol. 2007;20:84-9.
8. Kajiyama H, Shibata K, Terauchi M, Morita T, Ino K, Mizutani S, Kikkawa F. Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo. Clin Cancer Res. 2005;11:1798-808.
9. Fukusumi T, Ishii H, Konno M, Yasui T, Nakahara S, Takenaka Y, Yamamoto Y, Nishikawa S, Kano Y, Ogawa H, Hasegawa S, Hamabe A, Haraguchi N, Doki Y, Mori M, Inohara H. CD10 as a novel marker of therapeutic resistance and cancer stem cells in head and neck squamous cell carcinoma. Br J Cancer. 2014;111:506-14.
10. Dall'Era MA, True LD, Siegel AF, Porter MP, Sherertz TM, Liu AY. Differential expression of CD10 in prostate cancer and its clinical implication. BMC Urol. 2007;7:3.
11. Dakka N, Bellaoui H, Bouzid N, Khattab M, Bakri Y, Benjouad A. CD10 AND CD34 expression in childhood acute lymphoblastic leukemia in Morocco: clinical relevance and outcome. Pediatr Hematol Oncol. 2009;26:216-31.

Therapeutic

As an enzyme, inhibitors of CD10 are currently being used for therapy. Acertophan is used for treatment of acute diarrhea.¹ Sacubitril/valsartan, a dual agent that consists of the angiotensin II type 1 receptor blocker and a CD10 inhibitor, is administered in patients with chronic heart failure and reduced ejection fraction.^2-3 Furthermore, clinicals trials support the use of sacubitril/valsartan for treating hypertension.⁴

1. Baumer P, Danquechin Dorval E, Bertrand J, Vetel JM, Schwartz JC, Lecomte JM. Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea. Gut. 1992;33:753-8.
2. Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL ,Shi VC, Solomon SD, Swedberg K, Zile M, Andersen K, Arango JL, Arnold JM, Bělohlávek J, Böhm M, Boytsov S, Burgess LJ, Cabrera W, Calvo C, Chen CH, Dukat A, Duarte YC, Erglis A, Fu M, Gomez E, Gonzàlez-Medina A, Hagège AA, Huang J, Katova T, Kiatchoosakun S, Kim KS, Kozan Ö, Llamas EB, Martinez F, Merkely B, Mendoza I, Mosterd A, Negrusz-Kawecka M, Peuhkurinen K, Ramires FJ, Refsgaard J, Rosenthal A, Senni M, Sibulo AS Jr, Silva-Cardoso J, Squire IB, Starling RC, Teerlink JR, Vanhaecke J, Vinereanu D, Wong RC; PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.Circulation. 2015;131:54-61.
3. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure.  N Engl J Med. 2014;371:993-1004.
4. Chrysant SG. Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/valsartan. J Am Soc Hypertens. 2017;11:461-468.