CD31 PECAM-1(platelet endothelial cell adhesion molecule), GPIIa, endocam
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Platelet
Monocyte
Granulocyte
T Cell
Endothelial Cell
Leukocyte
Neutrophil
NK Cell
Endothelium
Lymphocyte
130 / 130
140 / 140

Expression
CD31 is expressed on vascular endothelium, platelets, leukocytes, and their precursors.  CD31 is expressed at high levels on all continuous endothelial, concentrated in junctions between endothelial cells in vitro, diffusely on monocytes, neutrophils, and NK cells and on subsets of T cells, but not on circulating B cells.


Structure
MOLECULAR FAMILY NAME: Belongs to the immunoglobulin supergene family.

CD31 is a single-pass type-1 glycoprotein.  It contains a 574 aa extracellular region which contains 6 Ig-like C2-type domains, has 9 consensus N-glycosylation sites and has a sequence similarity with the carcinoembryonic antigen CD66, CD56 NCAM and CD32, a transmembrane domain and a 118 aa cytoplasmic domain containing an ITIM motif and is serine and tyrosine phosphorylated following cellular activation, creating docking sites for SHP-2 and perhaps other cytosolic signaling molecules.  The N-linked glycosylated accounts for up to 20% of the molecular weight.  Domains 1 and 2 are required for homophilic binding.  It is possible that there is a disulfide bond between 4 and 5.

MOLECULAR MASS
Cell Type Unreduced Reduced
All 130-140 kDa 130-140 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 6 different isoforms.  Spliced mRNA missing the exon 9 transmembrane domain is present in varying levels in certain cell types and results in a soluble form.  The corresponding soluble protein lacking the transmembrane domain has been found in human serum.  Additional mRNAs encoding alternatively spliced forms with various cytoplasmic tail exons missing have been found by RT-PCR in human and mouse, however, proteins corresponding to these alternate forms have not yet been identified.

POST-TRANSLATIONAL MODIFICATION

N-linked glycosylation accounts for about 20% of its apparent molecular size.  Following cellular activation in different cell types, CD31 becomes phosphorylated on serine and tyrosine residues on its cytoplasmic domain.  CD31 may also become palmitoylated on cysteine residue 595.

Ligands
Alternative splicing gives rise to variants with different cytoplasmic regions and these give rise to specific binding characteristics.  CD31 binds SHP-1, PLC-g 1 and SHIP.

LIGANDS AND MOLECULES ASSOCIATED WITH CD31
Molecule Comment
Platelet endothelial cell adhesion 1 (PECAM-1) (CD31) Homophilic interaction
Heparin sulfate glycosaminoglycan chains (GAGs) Binding inferred, but controversial
a v/b 3 integrin Direct binding reported, but controversial
SHP-2 Docks on cytoplasmic tail


Function
CD31 has a role in transendothelial cell migration to sites of acute inflammation.  CD31 has been demonstrated to bind in a homophilic manner, binds on the apposing cell, and also mediates heterophilic interactions involving non-CD31 molecules.  The latter may be the result of direct binding of CD31 to another molecule, although this is controversial, or the result of secondary interactions mediated by non-CD31 receptors whose activation is CD31-dependent.  Cell-to-cell adhseion occurs via homophilic and heterophilic binding but ligands other than CD31 and CD38 have not been demonstrated.  Homophilic binding requires domains 1 and 2 and may play a role in vascular integrity and permeability.  CD31 mediates adhesion between cells that express CD31, endothelial cell-endothelial cell and leukocyte-endothelial cell.  CD31 has also been shown to have signaling functions that participate in an adhesion cascade.  Ligation of CD31 on leukocytes and platelets has been demonstrated to activate integrins of the b-1 T cells, b-2 T and NK cells, PMN, and monocytes, and b-2  platelet families.  MAbs to domain 6 are reported to enhance CD31 binding activity and augment platelet activation, which results in tyrosine phosphorylation of the CD31 cytoplasmic domain.  MAbs and recombinant CD31 proteins can inhibit neutrophil migration through blood vessels by blocking at the stage of interaction with the basement membrane.  CD31 may be a regulator of cell survival and apoptosis as the cytoplasmic region binds β- and γ-catenin, SHP-2, STAT3 and STAT5, all of which are involved in apoptopic and cell survival pathways.

BIOCHEMICAL ACTIVITY

CD31 is primarily an adhesion molecule with no enzymatic activity known.

DISEASE RELEVANCE AND FUNCTION OF CD31 IN INTACT ANIMAL

CD31 has a role in human tumor angiogenesis and suggests that CD31 participates in adhesive and/or signaling phenomena required for the motility and organization of endothelial cells.  CD31 is an adhesion molecule with no known enzymatic function and is involved in leukocyte trans-endothelial migration to sites of acute inflammation.  CD31 also has an important role in the diapedesis step of leukocyte emigration in inflammation.  CD31 antibodies block neutrophil PMN, monocyte, and NK cell diapedesis in vitro and in vivo, without affecting prior adhesion to the endothelium.  The amino terminal domains of both monocyte CD31 and endothelial cell CD31 appear to be involved in homophilic interaction necessary for transendothelial migration.  MAbs to the membrane-proximal domains of monocyte CD31 have been reported to block migration of monocytes across the subendothelial basal lamina presumably by blocking interaction of CD31 with non-CD31 molecules and/or blocking secondary effects of CD31 on the activation of other molecules.  CD31 is a minor histocompatibility antigen associated with graft versus host disease (GVHD) in bone marrow transplantation.  Knockout mice show defective transendothelial leukocyte migration as well as increased apoptopic cell death in liver, kidney and spleen, and elevated levels of TNF-α, IFN-γ, MCP-1, MCP-2, TNF receptors and IL-6.  Decreased levels of phoshorylated transcription factor STAT3 in CD31 knockout mice lead to greater susceptibility to endotoxic shock.


Comments
A Leu to Val polymorphism in CD31 residue 98 in the mature protein is a minor transplantation antigen where matching provides a significantly lower risk of graft-versus-host disease in bone marrow transplants.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD31
Molecule Comment
TATA-less promoter Transcription appears controlled in part by GATA element

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD31
Molecule Comment
Undefined serine kinase-perhaps PKC
Tyrosine kinase Src

ADDITIONAL INSIGHTS

CD31 possesses at least 3 activities. These direct participate in homophilic adhesion, in heterophilic adhesion, the precise mechanism(s) of which remains undefined and activation of integrins following CD31 crosslinking.  Different CD31-bearing cells may utilize different mechanisms at different times during interactions with different cells, so observations made in 1 cell system may not apply to others.  Important questions are under investigation.  How is CD31 adhesion regulated?  What are the downstream events that follow CD31 homophilic engagement?  Do alternatively spliced forms of CD31 protein exist in cells in functionally significant concentrations?  If so, how do they affect the physiology of the cell?


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 5175P16284
MouseQ08481L06039
Antibodies
CO.3E1D4   View Reactivity
JC/70A   View Reactivity
LCI-4   View Reactivity
LCI-9   View Reactivity
WM59   View Reactivity

Revised June 25, 2008


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