CD49d ITGA4 (integrin α4-chain), VLA-4α chain
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
T Cell
Reticulocyte
Lymph Node
NK Cell
Eosinophil
T Lymphocyte
B Lymphocyte
Monocyte
Basophil
Mast Cell
Thymocyte
Dendritic Cell
Melanoma Cell
Kupffer Cell
Muscle Cell
Lymphocyte
Erythroblast
Placenta
Myelomonocytic cell
Myeloblast
145 / 145
150 / 150
180 / 180

Expression
CD49d is expressed  broadly on T lymphocytes, memory T cells, naïve T, B lymphocytes, monocytes, eosinophils, basophils, mast cells, thymocytes, NK cells, dendritic cells, embryonic myeloblasts and myelomonocytic cells, some melanoma cells, Kupffer cells, muscle cells, erythroblastic precursor cells and sickle reticulocytes, but not on normal red blood cells, on platelets or on neutrophils except on rat neutrophils which express low levels of CD49d.  The mantle zone lymphocytes in lymph node stain more brightly than lymphocytes in the follicular centers or the interfollicular T-cell zones.



Structure
MOLECULAR FAMILY NAME: Belongs to the integrin a chain family.

CD49d is a single-pass type-1 999 aa glycoprotein.  It contains an extracellular region which contains more than 3 EF-hand-like divalent cation-binding sites, which modulate adhesion and 11 N-glycosylation sites, a transmembrane domain and a 32 aa cytoplasmic domain.  All integrin α chains have a conserved sequence found in the cytoplasmic domain immediately following the transmembrane domain (FYWS)-(RK)-x-G-F-F-x-R, which may be the motif involved in heterodimer formation.  CD49d does not belong to either of the 2 main groups of integrin a subunits because it contains neither the I-domain nor disulfide-linked cleavage sites found in some other integrin a chains.  On some cells, 145 kDa is partially cleaved into 2 fragments, 80 kDa N-terminal and 70 kDa C-terminal.  Cys278 and Cys717 are required for the optimal CD49d binding to CS-1 peptide.  A region including Arg89-Asp90 residues is involved in the homotypic cell aggregation and adhesion to CS-1 peptide, but not to VCAM-1. Tyr187 and Gly190 are critical for CS-1 and VCAM-1 binding.   CD49d migrates at either 150 kDa or 180 kDa in nonreducing SDS-PAGE.  The 180 kDa form requires unoxidized cysteines and divalent cations and is likely to be the functionally more important form of the molecule.  CD49d is an a4 integrin subunit which combines with CD29 to form VLA-4 (integrin α4/β1) complexes and with β7 integrin subunit to form the α4/β7 integrin.

MOLECULAR MASS
Cell Type Unreduced Reduced
Lymphocytes 145 kDa, 180 kDa 150 kDa

The core protein is 111 kDa and the 180 kDa isoform is called a4/180.  CD49d is associated with either 130 kDa b1 chain or 130 kDa b7 chain.

POST-TRANSCRIPTIONAL MODIFICATION: No information.

POST-TRANSLATIONAL MODIFICATION

CD49d consists of an 180 kDa conformational variant, called as a4 /180 kDa and the 145 kDa is cleaved to 80 kDa and 70 kDa fragments.  CD49d is activated to the adhesive configuration by multiple stimuli such as divalent cation, some CD29 mAb, CD3 mAb, CD31 mAb and chemokines.  The strengths of the stimulii are a divalent cation Mn2+ > CD29 mAb TS2/16 > TCR, CD31 and chemokines.

Ligands
Both CD49d/CD29 VLA-4 and the a4b7 integrin bind CD106 (VCAM-1) as well as an alternatively spliced form of fibronectin which contains the peptide CD319 (CS-1).  The a4b7 integrin also binds the mucosal addressin MAdCAM-1 and invasin.


LIGANDS AND MOLECULES ASSOCIATED WITH CD49d
Molecule Comment
CD106 (VCAM-1)           Ligand for a4b1 and  a4b7
MAdCAM-1 Ligand for a4b7
Fibronectin (CS-1) Ligand for a4b1 and a4b7, both
Cys278 and Cys717 are required
Invasin Microbial ligand
Thrombospondin a4b1

Homotypic aggregation involves a region including Arg89-Asp90 and is involved in the homotypic cell.



Function
CD49d participates in mononuclear cell trafficking to endoethelial sites of inflammation through the interaction with CD106 (VCAM-1).  CD49d acts as a receptor for fibronectin and has roles in cell-cell interactions and cell adhesion to the extracellular matrix.  CD49d functions in cell adhesion to cell surface ligands, VCAM-1a4b1 and a4b7 and MAdCAM-1 a4b7 and in cell adhesion to extracellular matrices, fibronectin a4b1 and a4b7 and thrombospondin a4b1.  Lymphocyte migration from circulation is into tissue by strengthening lymphocyte adhesion to endothelial cells.  CD49d provides a costimulatory signal with TCR-CD3 mediated signaling by inducing tyrosine phosphorylation of some focal adhesion proteins.  CD49d functions in regulating multiple inflammatory  responses by enhancing adhesion to and in the tethering or rolling of T cells in the vascular lumen on VCAM-1 of endothelium and the homing of T cell subsets to Peyer's patches by the binding of a4b7 to MAdCAM-1. T cell costimulation occurs with TCR-CD3-mediated signaling by inducing tyrosine phosphorylation of certain focal adhesion proteins such as phospholipase-Cg, pp125FAK, paxillin, 59Fyn/p56Lck, and mitogen-activated protein kinase.  Differentiation and traffic of hematopoietic precursor cells occurs by their adhesion to bone marrow stromal cells and the invasion of bacteria into cytoplasm through the a4b1 -binding to invasin.

BIOCHEMICAL ACTIVITY

The engagement of the a4b1 complex stimulates or co-stimulates with TCR-CD3-mediated signaling, tyrosine phosphorylation of focal adhesion kinase, pp125FAK, phospholipase Cg, paxillin, p59Fyn/p56Lck and mitogen-activated protein kinase in T cells.

DISEASE RELEVANCE AND FUNCTION OF CD49d IN INTACT ANIMAL

CD49d is important in normal placental development.  CD49d is involved in multiple inflammatory responses through the regulation of lymphocyte migration as well as T cell activation.  CD49d is essential to the differentiation and traffic of hematopoietic stem cells and is relevant to tumor progression and metastasis.  CD49d has a role in tumor progression and metastases that bind fibronectin, thrombospondin  and CD106.  CD49d is important for migration of chronic lymphocytic leukemia cells into lymph nodes.  Knockout mice show embryonic lethality and abnormal formation of heart and placenta.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD49d: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD49d: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3676P13612
MouseA41131Q00651X53176
Antibodies
9F10   View Reactivity
FW3-218   View Reactivity
HP2/1   View Reactivity
P4G9   View Reactivity

Revised June 25, 2008


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