CD38 is a novel multifunctional ectoenzyme widely expressed in cells and tissues especially in leukocytes. CD38 also functions in cell adhesion,signal transduction and calcium signaling

• CD38 [HUGO gene name]
• T10
• ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase

MAJOR LINKS FOR CD38  

• NCBI LocusLink Record: 952
• Mendelian Inheritance in Man (OMIM): 107270
• SwissProt annotated protein record: P28907

• CD38 is a novel enzyme capable of catalysing multiple reactions, including NAD glycohydrolase, ADP-ribosyl cyclase, cyclic ADP ribose hydrolase and base-exchange activities
• Two of the enzymatic products, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), are calcium messengers in a wide variety of cells from protist, plant, and mammal to human*

CELLULAR FUNCTION OF CD38  

• Positive and negative regulator of cell activation and proliferation, depending on the cellular environment
• Involved in adhesion between human lymphocytes and endothelial cells
• Involved in the metabolism of two calcium messengers, cADPR and NAADP**

DISEASE RELEVANCE OF CD38 AND FUNCTION OF CD38 IN INTACT ANIMAL  

• Leukemia phenotyping and classification
• Monitoring of HIV-1 infection and progression
• Targeting of immunotoxin antibody in the treatment of myeloma
• Presence of autoantibodies with anti-CD38 specificity in patients with type II diabetes mellitus
• In mice, T-independent immune responses

• Families in which CD38 is a member
  • CD38-->ADP-ribosyl cyclase
  • CD38-->ectoenzyme

MOLECULAR STRUCTURE OF CD38  

• Single chain type II transmembrane molecule (300 amino acids)
• 256 amino acids extracellular region
• 21 amino acids intracellular region
• 23 amino acids transmembrane region

MOLECULAR MASS OF CD38  

POST-TRANSCRIPTIONAL MODIFICATION OF CD38  

• CD38alt: Splice form lacking exon 3; the ensuing frame-shift leads to a premature stop codon

POST-TRANSLATIONAL MODIFICATION OF CD38  

• The native 45 kDa form is modified by ATRA-induced differentiation to produce a 190 kDa form

SUBSTRATES FOR CD38  

ENZYMES WHICH MODIFY CD38   - No information

LIGANDS FOR CD38 AND MOLECULES ASSOCIATED WITH CD38  

• NOTE: Laterally associated with CD38 on the cell surface

• Expressed at variable levels on the majority of hemopoietic cells, prevalently during early differentiation and activation
• Expressed at high levels on plasma cells
• Constitutively expressed also in brain, muscle, kidney and other tissues*

• The biological role of the molecule is still controversial
• CD38 seems to act as a channel that delivers activation signals in T, B, NK cells and monocytes, inducing cytokine production and secretion, and modulation of cytoplasmic calcium fluxes
• Germinal center B cells (mature B lymphocytes) are rescued from apoptosis by CD38-mediated signaling. Conversely, CD38 is a messenger of death for human B cell precursors in bone marrow where ligation of CD38 inhibits proliferation and induces apoptosis
• Signals mediated by CD38 ligation are reported to induce phosphorylation of several substrates, including c-cbl, syk, p85 subunit of phosphatidylinositol 3-kinase and phospholipase C-gamma
• Surface CD38 is reported to act as a modulator of homotypic and heterotypic cellular interactions, mostly studied in T and endothelialcells. These studies led to the identification of CD31, an Ig superfamily member, as a counter-receptor for CD38
• The extracellular portion of CD38 is endowed with multiple enzymatic activities which include the hydrolysis of NAD+ and synthesis of cADPR, NAADP and ADP-ribose. NAADP and cADPR are calcium messengers*
• CD38 signaling is mediated by a pathway requiring the B cell receptor(BCR) or T cell receptor (TCR) for its implementation. The enzymatic activity of CD38 does not apparently contribute to its signaling capacity
• CD38 participates in the regulation of T cell-mediated cytotoxicity
• The CD38 gene is located on 4p15, close to the gene for CD157. The CD38 gene has a bi-allelic intronic PvuII polymorphism. In the Caucasian population, the two alleles, CD38*A and CD38*B, have a frequency of 15 and 85%, respectively

SELECTION OF OTHER CD38-SPECIFIC REFERENCE MAB  

REVIEWS

1. Ferrero E; Malavasi F. The metamorphosis of a molecule: from soluble enzyme to the leukocyte receptor CD38. J. Leukoc. Biol. 1999 65:151 PubMed

2. Lund F; Solvason N; Grimaldi JC; Parkhouse RM; Howard M. Murine CD38: an immunoregulatory ectoenzyme. Immunol. Today 1995 16:469 PubMed

3. Malavasi F; Funaro A; Roggero S; Horenstein A; Calosso L; Mehta K. Human CD38: a glycoprotein in search of a function. Immunol. Today 1994 15:95 PubMed

4. Mehta K; Shahid U; Malavasi F. Human CD38, a cell-surface protein with multiple functions. FASEB J. 1996 10:1408 PubMed

5. Shubinsky G; Schlesinger M. The CD38 lymphocyte differentiation marker: new insight into its ectoenzymatic activity and its role as a signal transducer. Immunity 1997 7:315 PubMed

PRIMARY CITATIONS

6. Aarhus R; Graeff RM; Dickey DM; Walseth TF; Lee HC. ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from NADP. J. Biol. Chem. 1995 270:30327 ** PubMed

7. Cesano A; Visonneau S; Deaglio S; Malavasi F; Santoli D. Role of CD38 and its ligand in the regulation of MHC-nonrestricted cytotoxic T cells. J. Immunol. 1998 160:1106 PubMed

8. Cockayne DA; Muchamuel T; Grimaldi JC; Muller-Steffner H; Randall TD; Lund FE; Murray R; Schuber F; Howard MC. Mice deficient for the ecto-nicotinamide adenine dinucleotide glycohydrolase CD38 exhibit altered humoral immune responses. Blood 1998 92:1324 PubMed

9. Deaglio S; Morra M; Mallone R; Ausiello CM; Prager E; Garbarino G; Dianzani U; Stockinger H; Malavasi F. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J. Immunol. 1998 160:395 PubMed

10. Deterre P; Gelman L; Gary-Gouy H; Arrieumerlou C; Berthelier V; Tixier JM; Ktorza S; Goding J; Schmitt C; Bismuth G. Coordinated regulation in human T cells of nucleotide-hydrolyzing ecto-enzymatic activities, including CD38 and PC-1. Possible role in the recycling of nicotinamide adenine dinucleotide metabolites. J. Immunol. 1996 157:1381 PubMed

11. Ferrero E; Malavasi F. Human CD38, a leukocyte receptor and ectoenzyme, is a member of a novel eukaryotic gene family of nicotinamide adenine dinucleotide+-converting enzymes: extensive structural homology with the genes for murine bone marrow stromal cell antigen 1 and aplysian ADP-ribosyl cyclase. J. Immunol. 1997 159:3858 PubMed

12. Ferrero E; Saccucci F; Malavasi F. The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene. Immunogenetics 1999 49:597 PubMed

13. Funaro A; Reinis M; Trubiani O; Santi S; Di Primio R; Malavasi F. CD38 functions are regulated through an internalization step. J. Immunol. 1998 160:2238 PubMed

14. Hoshino S; Kukimoto I; Kontani K; Inoue S; Kanda Y; Malavasi F; Katada T. Mapping of the catalytic and epitopic sites of human CD38/NAD+ glycohydrolase to a functional domain in the carboxyl terminus. J. Immunol. 1997 158:741 PubMed

15. Howard M; Grimaldi JC; Bazan JF; Lund FE; Santos-Argumedo L; Parkhouse RM; Walseth TF; Lee HC. Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science 1993 262:1056 PubMed

16. Ikehata F; Satoh J; Nata K; Tohgo A; Nakazawa T; Kato I; Kobayashi S; Akiyama T; Takasawa S; Toyota T; Okamoto H. Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients. J. Clin. Invest. 1998 102:395 PubMed

17. Kato I; Yamamoto Y; Fujimura M; Noguchi N; Takasawa S; Okamoto H. CD38 disruption impairs glucose-induced increases in cyclic ADP-ribose, [Ca2+]i, and insulin secretion. J. Biol. Chem. 1999 274:1869 PubMed

18. Kitanaka A; Suzuki T; Ito C; Nishigaki H; Coustan-Smith E; Tanaka T; Kubota Y; Campana D. CD38-mediated signaling events in murine pro-B cells expressing human CD38 with or without its cytoplasmic domain. J. Immunol. 1999 162:1952 PubMed

19. Kontani K; Nishina H; Ohoka Y; Takahashi K; Katada T. NAD glycohydrolase specifically induced by retinoic acid in human leukemic HL-60 cells. Identification of the NAD glycohydrolase as leukocyte cell surface antigen CD38. J. Biol. Chem. 1993 268:16895 PubMed

20. Mallone R; Ferrua S; Morra M; Zocchi E; Mehta K; Notarangelo LD; Malavasi F. Characterization of a CD38-like 78-kilodalton soluble protein released from B cell lines derived from patients with X-linked agammaglobulinemia. J. Clin. Invest. 1998 101:2821 PubMed

21. Morra M; Zubiaur M; Terhorst C; Sancho J; Malavasi F. CD38 is functionally dependent on the TCR/CD3 complex in human T cells. FASEB J. 1998 12:581 PubMed

22. Nata K; Takamura T; Karasawa T; Kumagai T; Hashioka W; Tohgo A; Yonekura H; Takasawa S; Nakamura S; Okamoto H. Human gene encoding CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase): organization, nucleotide sequence and alternative splicing. Gene 1997 186:285 PubMed

23. Prasad GS; McRee DE; Stura EA; Levitt DG; Lee HC; Stout CD. Crystal structure of Aplysia ADP ribosyl cyclase, a homologue of the bifunctional ectozyme CD38. Nat. Struct. Biol. 1996 3:957 PubMed

24. States DJ; Walseth TF; Lee HC. Similarities in amino acid sequences of Aplysia ADP-ribosyl cyclase and human lymphocyte antigen CD38. Trends Biochem. Sci. 1992 17:495 PubMed

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Portions copyright by Garland Press and by the International Workshops on Human Leukocyte Differentiation Antigens; used with permission

Modified 10/25/99   mpr@mail.nih.gov