CD143 ACE(angiotensin converting enzyme, pepitidyl-dipeptidase A)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Endothelial Cell
Epithelial Cell
Neuronal Cell
Fibroblast
Macrophage
Prostate
Lung
Kidney
Heart
Small intestine
Chondrocyte
Kupffer Cell
90 / 90
170 / 170

Expression
In human endothelial cells, immunohistochemically detectable CD143 is restricted with a few exceptions.  The endothelial expression of CD143 is heterogeneous and strongest in arterioles and small muscular arteries whereas endothelial cells of large arteries and veins lack it most often completely. There are 2 further organ-specific exceptions which are remarkable.  The normal capillary endothelial cells of the lung expressed CD143 strongly and homogeneously, while those of the normal human kidney are negative including all intraparenchymal vessels.  CD143 is most prominent on endothelial cells detectable at the brush border epithelium of proximal renal tubules, at the brush borders of enterocytes in the small intestine and at microvilli structures of ductuli efferentia of the epididymis, neuronal cells, fibroblasts, activated macrophages. Kupfer cells, CD2+ T cells and immature chondrocytes.  CD143 occurs on neuronal cells accentuated in the neuropile of basal ganglia such as nucleus caudatus, putamen, and pallidum, the substantia nigra, magnocellular hypothalamus, colliculi superior and inferior of brain stem and to a less extent, in thalamus and in substantia granulosum cerebelli.  Leydig cells in testis and granulosa cells of ovary express somatic form of CD143.  On other non-endothelial mesenchymal tissues CD143 might be found to a variable degree.  They are found on fibrocytes/blasts of loose connective tissue and adventitia of vessels, on activated macrophages/histiocytes, CD11b/CD18+ cells, weak on Kupfer's cells in liver and on some T-lymphocytes.  The germinal form of CD143 is exclusively found in differentiating germinal cells that is in round spermatides and spermatozoa.  In human, high expression was found in kidney, heart, gastrointestinal system and prostate.  A weak level of CD143 expression has been found in glandular epithelial cells of cutaneous adnexes, breast, salivary and adrenal glands, as well as very faint in the prostatic epithelium.  In epithelial cells of choroid plexus and in ependym, CD143 expression seems to be age-dependent.



Structure
MOLECULAR FAMILY NAME: Belongs to the metallopeptidase family.

CD143 is a single-pass type-1 glycoprotein.  It contains 2 forms of the polypeptide, a 1306 aa human somatic form in a single polypeptide chain which has highly homologous internal N-terminal and C-terminal domains each with a catalytic site and contains 15 potential N-linked glycosylation sites and a 732 aa germinal testicular form that has a single catalytic site that corresponds to one C-terminal domains of the somatic form and has 7 potential potential N-linked glycosylation sites and a serine/threonine-rich region in the N-terminus which is O-glycosylated.  Both forms are anchored in the plasma membrane and encoded by a hydrophobic transmembrane polypeptide but are transcribed from different promoters.   The two domains of CD143 differ in conformation and immunological properties and in their affinity to bind several inhibitors.  The solubel forms of CD143 are detected in plasma, urine, amniotic and cerebrospinal fluids and seminal plasma.  The human CD143 gene spans 21 kb and comprises 26 exons.  The somatic promoter located in the 5'-flanking region of the first exon and a promoter for germinal CD143 mRNA situated in intron 12.

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Somatic form of CD143 170 (180) kDa 170 (180) kDa
Germinal (testicular) form of CD143 90 (110) kDa 90 (110) kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms, a somatic form and a testicular form that are equally active.  Somatic CD143 mRNA is transcribed from exon 1 to exon 26 and exon 13 is removed by splicing from the primary RNA transcript.  The germinal CD143 mRNA is transcribed from exon 13 to 26.

POST-TRANSLATIONAL MODIFICATION

Somatic CD143 contains a 17 potential N-linked glycosylation site.  Germinal testicular CD143 has 7 potential N-linked glycosylation sites and contains a Ser/Thr-rich region at the extended CD143 N-terminus which is O-glycosylated.  Both forms of CD143 have a N-terminal signal sequence for translocation of the ectoenzyme to the plasma membrane and which are absent in the mature proteins with 29 residues-somatic CD143 and 21-germinal. Besides being bound to the plasma membrane, CD143 also exists in soluble forms in plasma, urine, amniotic and cerebrospinal fluids and seminal plasma.  The plasma CD143 is probably derived from vascular endothelial cells and lacks the carboxy terminus of CD143.  The cleavage site is between Arg 1137 and Leu 1138.

Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD143

CD143 binds angiotensin I and bradkinin.  CD143 binds 2 zinc ions and 2 chloride ions per subunit.  CD143 is a ligand for lung-specific delivery of substances of isotopes, drugs and genes conjugated with mAb to CD143, 9B9.  CD143, ACE, is necessary for spermatozoa to bind to the egg.  Spermatozoa cells not expressing CD143 bind in numbers 10 times less than normal.  CD143 also appears to determine the success of the spermatozoa in penetrating the egg.



Function
CD143 is a zinc metallopeptidase that metabolizes angiotensin and bradykinin but also cleaves C-terminal dipeptides from various oligopeptides as well as various oligopeptides from substance P and LH-RH.  CD143 encodes an enzyme involved in the conversion of angiotensin I into a physiologically active peptide angiotensin II.  Angiotensin II is a potent vasopressor and aldosterone-stumlating peptide that controls blood pressure and fluid-electrolyte baclance.  This enzyme plays a role in the renin-angiotensin system.            

BIOCHEMICAL ACTIVITY

CD143 is an angiotensin converting enzyme which acts primarily as a peptidyl dipeptide hydrolase that is necessary for spermatozoa to bind to eggs and subsequent peneration and is involved in the metabolism of 2 major vaso-active peptides, angiotensin 2 and bradykinin.  CD143 also cleaves C-terminal dipeptides from various oligopeptides with a free C-terminus and protected tripeptides from substance P and LH-RH.

DISEASE RELEVANCE AND FUNCTION OF CD143 IN INTACT ANIMAL

CD143 plays an important role in blood pressure regulation and electrolyte balance by hydrolyzing angiotensin I into angiotensin II, a potent vasopressor and an aldosterone stimulating peptide.  There is polymorphism in the CD143 gene, consisting of the insertion or deletion of 287 base pair DNA fragments in intron 16, an Alu repetitive sequence.  The insertion/deletion polymorphism accounts for 20% of CD143 level variance in the blood and tissues among individuals.  The highest CD143 activity was found in the individuals bearing deletion genotype, 70% as high as that of subjects with the insertion genotype.  The deletion genotype is associated with myocardial infarction, strokes, diabetic nephropathy and other cardiovascular complications and CD143 activity and concentration are useful prognostic indicators.  The fertility of homozygous male mice mutants with disrupted CD143 gene was greatly reduced, whereas all homozygous female mutants were fertile.

Comments

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD143

Molecule Comment
SP-1 binding sites 3 potential sites
GRE (glucocorticoid-responsive elements) 4 GRE sites
cAMP-responsive element
Steroid responsive element

Somatic CD143 expression is regulated by glucocorticoids, thyroid hormones, and cAMP-related agents.  The somatic CD143 promoter has 3 SP1 potential binding sites and 4 glucocorticoid-responsive elements.  The level of germinal CD143 expression is known to be under the control of androgens and is increased dramatically at puberty.  The germinal CD143 promoter has cAMP-responsive and steroid-responsive elements.

SUBSTRATES
Molecule Comment
Angiotensin I Major vaso-active peptide
Bradykinin Major vaso-active peptide
Substance P
LH-RH
Hip-His-Leu
Z-Phe-His-Leu
N-Acetyl-Ser-Asp-Lys-Pro

N- and C-domains of CD143 displayed a different substrate specificity.  Rates of hydrolysis of Hip-His-Leu, angiotensin I, substance P and bradykinin by the C-domain of CD143 were 9, 3, 3 and 1.5 times higher than by the N-domain, respectively.  Z-Phe-His-Leu was cleaved equally by both domains.  N-Acetyl-Ser-Asp-Lys-Pro, the hematopoietic peptide and LH-RH hydrolyzed 40 and 30 times faster by the N-domain of CD143 than by the C- domain.

ENZYMES WHICH MODIFY CD143: No information.

ADDITIONAL INSIGHTS

Studies and data show that the CD143 phenotype, activity or concentration, might be a more sensitive marker of various cardiovascular complications than the CD143 genotype.  Studies of CD143 I/D polymorphism and beneficial therapeutic effect of CD143 inhibitors suggest that CD143 might be a new risk factor for various cardiovascular diseases.  The immunohistochemical staining of more than 2000 specimens of human tissues by a set of mAbs to CD143 showed prominent local changes of expression in pathology.  In sudden cardiac death and vascularization of neoplasias, it has been found significant in an increase of endothelial CD143, whereas loss of endothelial CD143 has been noted in acute, non-specific inflammations.  Strong CD143 over expression within the vascular wall has been detected already in the onset of atherosclerosis and may contribute to fibrogenesis during vascular remodeling.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 1636P12821
Antibodies
2E2   View Reactivity
3C5   View Reactivity
9B9   View Reactivity
I2H5   View Reactivity

Revised June 25, 2008


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