• Alpha-4 integrin chain
• VLA-4 alpha chain

MAJOR LINKS FOR CD49d  

• NCBI LocusLink Record: 3676
• Mendelian Inheritance in Man (OMIM): 192975
• SwissProt annotated protein record: P13612

• 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

CELLULAR FUNCTION OF CD49d  

• Cell adhesion to cell surface ligands, VCAM-1 (a4b1 and a4b7) and MAdCAM-1
• (a4b7)
• Cell adhesion to extracellular matrices, fibronectin (a4b1 and a4b7), thrombospondin (a4b1)
• Lymphocyte migration from circulation into tissue by strengthening lymphocyte adhesion to endothelial cells
• Tethering or rolling of T cells in the vascular lumen on VCAM-1 of endothelium
• Homing of T cell subsets to Peyer's patches by the binding of a4b7 to MAdCAM-1
• T cell costimulation with TCR-CD3-mediated signaling by inducing tyrosine phosphorylation of certain focal adhesion proteins such as phospholipase-Cg, pp125FAK, paxillin, p59fyn/p56lck, mitogen-activated protein kinase
• Differentiation and traffic of hematopoietic precursor cells by their adhesion to bone marrow stromal cells
• Invasion of bacteria into cytoplasm through the a4b1-binding to invasin

DISEASE RELEVANCE OF CD49d AND FUNCTION OF CD49d IN INTACT ANIMAL  

• 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
• CD49d is relevant to tumor progression and metastasis

• Families in which CD49d is a member
  • CD49d-->integrin alpha chains-->integrin assemblies

MOLECULAR STRUCTURE OF CD49d  

• The extracellular region includes more than 3 EF-hand-like divalent cation-binding sites, which modulate adhesion
• 11 N-glycosylation sites in extracellular region
• Extracellular region contains neither I-domain nor disulfide-linked cleavage site found in some other integrin alpha chains
• On some cells 145kd is partially cleaved into two 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*
• Tyr 187 and Gly 190 are critical for CS-1 and VCAM-1 binding **

MOLECULAR MASS OF CD49d  

• Core protein is 111 kDa
• 180 kDa isoform, called a4/180
• CD49d associated with either 130 kDa b1 chain or 130 kDa b7 chain

POST-TRANSCRIPTIONAL MODIFICATION OF CD49d   - Unknown

POST-TRANSLATIONAL MODIFICATION OF CD49d  

• 180 kDa conformational variant, called as a4/180
• 145kDa cleaved to 80 and 70 kDa fragments
• CD49d is activated to adhesive configuration by multiple stimuli such as divalent cation, some CD29 mAb, CD3 mAb, CD31 mAb and chemokines
• Strength of the stimuli: divalent cation Mn2+ > CD29 mAb TS2/16 > TCR, CD31 and chemokine

SUBSTRATES FOR CD49d   - No information

ENZYMES WHICH MODIFY CD49d   - Unknown

LIGANDS FOR CD49d AND MOLECULES ASSOCIATED WITH CD49d  

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

• Broad type of cells including T lymphocytes (memory T > naive T)
• B lymphocytes
• Monocytes
• Eosinophils
• Basophils
• Mast cells
• Thymocytes,
• NK cells
• Dendritic cells
• Embryo myeloblasts, myelomonocytic cells
• Some melanoma cells, Kupffer cells, muscle cells
• Erythroblastic precursor cells and sickle reticulocytes, but not on normal red blood cells
• Not on platelets
• Not on neutrophils (except rat neutrophils express low levels of CD49d)*
• Mantle zone lymphocytes in lymph node stain more brightly than lymphocytes in the follicular centers or the interfollicular T-cell zones

SELECTION OF OTHER CD49d-SPECIFIC REFERENCE MAB  

REVIEWS

1. Elices, M.J. ed. 1995. Springer Semin. Immunopathol. 16. Number 4 **

2. Hemler ME, Kassner P, Bodorova J. In Leukocyte typin V (ed SF Schlossman et al.), pp1617-18. Oxford University Press, Oxford (1993).

3. Lobb RR,Hemler ME The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest 1994 94:1722 PubMed

PRIMARY CITATIONS

4. Alon R,Kassner PD,Carr MW,Finger EB,Hemler ME,Springer TA The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol 1995 128:1243 PubMed

5. Arroyo AG,Yang JT,Rayburn H,Hynes RO Differential requirements for alpha4 integrins during fetal and adult hematopoiesis. Cell 1996 85:997 ** PubMed

6. Berlin C,Berg EL,Briskin MJ,Andrew DP,Kilshaw PJ,Holzmann B,Weissman IL,Hamann A,Butcher EC Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993 74:185 PubMed

7. Ennis E,Isberg RR,Shimizu Y Very late antigen 4-dependent adhesion and costimulation of resting human T cells by the bacterial beta 1 integrin ligand invasin. J Exp Med 1993 177:207 PubMed

8. Maguire JE,Danahey KM,Burkly LC,van Seventer GA T cell receptor- and beta 1 integrin-mediated signals synergize to induce tyrosine phosphorylation of focal adhesion kinase (pp125FAK) in human T cells. J Exp Med 1995 182:2079 PubMed

9. Masumoto A,Hemler ME Mutation of putative divalent cation sites in the alpha 4 subunit of the integrin VLA-4: distinct effects on adhesion to CS1/fibronectin, J Cell Biol 1993 123:245 PubMed

10. Pulido R,Elices MJ,Campanero MR,Osborn L,Schiffer S,Garcia-Pardo A,Lobb R,Hemler ME,Sanchez-Madrid F Functional evidence for three distinct and independently inhibitable adhesion activities mediated by the human integrin VLA-4. Correlation with distinct alpha 4 epitopes. J Biol Chem 1991 266:10241 ** PubMed

11. Schweighoffer T,Tanaka Y,Tidswell M,Erle DJ,Horgan KJ,Luce GE,Lazarovits AI,Buck D,Shaw S Selective expression of integrin alpha 4 beta 7 on a subset of human CD4+ memory T cells with Hallmarks of gut-trophism. J Immunol 1993 151:717 PubMed

WWW RESOURCES

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

Modified 10/14/99   mpr@mail.nih.gov