CD38 T10, ADP-ribosyl cyclase, gp45
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 2 glycoprotein
Kidney
Placenta
Pancreas
B Cell
Thymocyte
T Cell
Plasma Cell
Monocyte
NK Cell
Erythroid Cell
Myeloid Cell
Bone Marrow
Brain
Lymphoid Cell
Leukocyte
Skeletal muscle
Ovary
Neuroblastoma cell
Testis
Hematopoietic Cell
39 / 39
45 / 45
78 / 78
190 / 190

Expression
CD38 is expressed in early stages of CD34+ progenitor into commited erythroid, lymphoid and myeloid precursors of the immune system and is widely expressed in cells and tissues especially in leukocytes.  CD38 is expressed at variable levels on the majority of hematopoietic cells, prevalently during early differentiation and activation and some non-hematopoietic cells.  It is expressed at high levels on plasma cells and constitutively expressed in the brain, muscle, bone marrow, pancreas, testis, ovary, placenta, kidney, malignant lymphoma, neuroblastoma and other tissues.  It is expressed on high levels of early B and T cells, activated T cells, germinal center B cells and NK cells.  There is a 50-80% occurance of mononuclear cells in the first 3 years of life with a gradual decline thereafter.  Tissues are high with glucose metabolism.

ononuclear cells 

Structure
MOLECULAR FAMILY NAME: Belongs to the ADP-ribosyl cyclase family.

CD38 is a single-pass type-2 300 aa glycoprotein.  It contains a 256 aa extracellular region which contains 2 hyaluronic acid binding sites, 11 conserved cysteines, 4 of which are necessary for synthesis and hydrolysis of cADPR and several leucines, a 21 aa transmembrane domain which can potentially form leucine zipper motifs that may allow interaction of CD38 with other molecules and a 23 aa N- terminal intracellular cytoplasmic domain containing no motifs known to associate with signaling molecules.  The soluble form found in serum exists as either monomer or dimer, both of which have normal enzymatic activity.  CD38 lacks homology to immunoglobulin superfamily or MHC molecules.

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Leukocytes 45 kDa 45 kDa
HL-60 45 kDa, 190 kDa After all-trans-retinoic acid (ATRA) differentiation
Soluble form 39 kDa 39 kDa
Soluble form 78 kDa 78 kDa In X-linked agammaglobulinemia (XLA)-derived B cell lines

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  CD38alt- splice form lacks exon 3. The ensuing frame-shift leads to a premature stop condon.

POST-TRANSLATIONAL MODIFICATION

The native 45 kDa form is modified on myeloid leukemic cells by ATRA-induced differentiation to produce a 190 kDa form.


Ligands
CD38 binds hyaluronic acid and CD31.  The Moon-1 mAb blocks CD38-mediated binding of several cell lines to human vein endothelial cells.  Moon-1 recognizes a molecule of 120 kDa expressed on endothelium, monocytes, platelets, NK cells, T and B cells.

LIGANDS AND MOLECULES ASSOCIATED WITH CD38
Molecule Comment
CD31 Binds CD38
Hyaluronic acid Binds CD38
T cell receptor (TCR)/CD3 Laterally associated with CD38 on the cell surface
B cell receptor (BCR) Laterally associated with CD38 on the cell surface
CD16 Laterally associated with CD38 on the cell surface
CD73 Laterally associated with CD38 on the cell surface
PC-1 Laterally associated with CD38 on the cell surface
CD26 Laterally associated with CD38 on the cell surface


Function
CD38 is a multifunctional molecule involved  in cell adhesion, activation, proliferation, adhesion, signal transduction and calcium signaling depending on the cellular envinviroment.  It acts as an ectoenzyme and cytosolic enzyme involved in the metabolism of nucleotides and as an adhesion receptor.  CD38 is able to bind CD31 enabling adherence of lymphocytes to endothelial cell and can bind hyaluronic acid in the extracellular matrix.  The ectoenzymatic activity is involved in the production of calcium mobilizing compounds CD38/CD31 cognate interactions initating a multistep signaling pathway resulting in the internalization of CD38 and cytokine release.  The extracellular portion of CD38 appears to act as a channel that allows activation signals to enter monocytes, NK, T and B cells resulting in synthesis and release of cytokine and cytoplasmic calcium fluxes.  It is involved in adhesion between human lymphocytes, endothelial cells and in the metabolism of the  2 calcium messengers, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP).  NAADP and cADPR are calcium messengers.  It is a bifunctional enzyme that can synthesize cADPR from nicotinamide adenine dinucleotide (NAD+) as well as hydrolyze cADPR to ADP-ribose.  As such, CD38 might mediate ADP-ribosylation of an as yet uncharacterized physiologic target molecule.  Antibodies to human and mouse CD38 have a wide range of biological effects, including the induction of B and T cell proliferation, protection of B cells from apoptosis, inhibition of B lymphopoiesis and enhancement of macrophage APC function.  Germinal center B cells, mature B lymphocytes, are rescued from apoptosis by CD38-mediating signaling.  Conversely, CD38 is a messenger of death for human B cell precurors in bone marrow where ligation of CD38 inhibits and induces apoptosis.  Data indicates that the signaling activity of CD38 in T cells is dependent on the presence of a functional TCR/CD3 complex on the T cell membrane which likely specialized signal transducing units together with CD38.  There is an impression that CD38 controls the homing process mainly through the interaction with the CD31 counter receptor expressed by endothelial and other cells and the binding to CD31 enables the adherence of lymphocytes to endothelial cell and can bind hyalurionic acid in the extracellular matrix.  Signaling through CD38 results in Tyr phosphorylation, and activation of the protein kinase Syk, the c-cbl proto-oncogene and Bruton Tyr kinase.  CD38 regulates T cell mediated cytotoxicity and ligation induces cell activation and proliferation or death depending on the cellular enviroment.  Knockout mice show deficiencies in enzyme activities.

BIOCHEMICAL ACTIVITY

CD38 is a novel enzyme capable of catalysing multiple reactions, including NAD glycohydrolase, ADP-ribosyl cyclase, cyclic ADP ribose hydrolase and base-exchange activities.  There are 2 of the enzymatic products, cADPR and NAADP, are calcium messengers in a wide variety of cells from protist, plant and mammal to human.

DISEASE RELEVANCE AND FUNCTION OF CD38 IN INTACT ANIMAL

CD38 functions as a phenotypic and prognostic marker in leukemia  monitoring of HIV-1 infection and progression.  It is used to purify bone marrow and germinal center subsets and is a target of immunotherapy and targets the immunotoxin antibody in the treatment of myeloma.  The presence of anti-CD38 antibodies are found specificity in patients with type-1 and type-2 diabetes mellitus.

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD38
Molecule Comment
Retinoids in HL-60 myeloid cell line Upregulation
Vitamin D3 in Jurkat T cell line Upregulation
g-interferon in human monocytes Upregulation

SUBSTRATES
Molecule Comment
b-nicotinamide adenine dinucleotide (b-NAD+)
b-nicotinamide adenine dinucleotide phosphate (b-NADP)
Cyclic ADP-ribose (cADPR)

ENZYMES WHICH MODIFY CD38: No information.



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 952P28907
MouseJ49586L11332
RatJC2410D30795
Antibodies
AT 13/5   View Reactivity
HIT2   View Reactivity

Revised June 25, 2008


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