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Gene Review

ICAM4  -  intercellular adhesion molecule 4...

Homo sapiens

Synonyms: CD242, ICAM-4, Intercellular adhesion molecule 4, LW, LW blood group protein, ...
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Disease relevance of ICAM4

  • Although normal RBCs are considered passively entrapped in fibrin polymers during thrombus, these studies identify ICAM-4 as the first RBC protein ligand of platelets that may have relevant physiological significance [1].
  • This finding also confirms the presence of a larger linkage group on chromosome 19, including now the loci for apoE, Le, C3, LW, Lu, Se, H, PEPD, myotonic dystrophy (DM), neurofibromatosis (NF) and familial hypercholesterolemia (FHC) [2].

High impact information on ICAM4


Chemical compound and disease context of ICAM4


Biological context of ICAM4

  • High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5 [6].
  • Deletion of individual Ig domains of ICAM-4 and inhibition by synthetic peptides showed that the alpha(IIb)beta(3) integrin binding site encompassed the first and second Ig domains and that the G65-V74 sequence of domain D1 might play a role in this interaction [1].
  • These findings suggest a role for ICAM-4 in normal erythropoiesis and may also be relevant to the adhesive interactions of sickle cells [7].
  • No detectable abnormality of the LW gene or transcript could be detected in another LW(a- b-) individual (Nic), suggesting the heterogeneity of these phenotypes [8].
  • In addition, the LW locus has been assigned to chromosome 19p13.3 by in situ hybridization [9].

Anatomical context of ICAM4


Associations of ICAM4 with chemical compounds

  • Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3 integrin [1].
  • The platelet fibrinogen receptor alpha(IIb)beta(3) (platelet GPIIb-IIIa) in a high affinity state following GRGDSP peptide activation was identified for the first time as the receptor for RBC ICAM-4 [1].
  • ICAM-4 lacks such a residue, which is replaced by an arginine [13].
  • The LW blood group glycoprotein is homologous to intercellular adhesion molecules [4].
  • Linkage of the LW blood group locus with the complement C3 and Lutheran blood group loci [2].

Physical interactions of ICAM4

  • However, the ICAM-4 binding region in both I domains seems to overlap with the regions recognized by the ICAM-1 and ICAM-2 [13].
  • Deletion of the individual immunoglobulin domains of ICAM-4 demonstrated that both its domains contain binding sites for CD11c/CD18 [5].
  • Our results provide evidence that the beta3 integrin binding sites encompass the first and second Ig-like domains of ICAM-4 [14].

Other interactions of ICAM4

  • Competition experiments indicated that the binding sites in ICAM-4 for the CD11a and CD11b I domains are different [13].
  • Based on the crystal structure of ICAM-2, we propose a model for the Ig-like domains D1 and D2 of ICAM-4 [15].
  • This group includes the Rh50 glycoprotein, LW glycoprotein, glycophorin B, Duffy glycoprotein, and CD47 glycoprotein [16].
  • In addition, several membrane components including the Rh proteins and other glycoproteins recently characterized (Rh50 glycoprotein, CD47, glycophorin B, Duffy, LW) are absent or severely decreased on these cells [17].
  • No obvious abnormality of the LW gene, including the 5'UT region, has been detected by sequencing polymerase chain reaction-amplified genomic DNA from RhD+ or RhD- donors and from an Rhnull variant that lacks the Rh and LW proteins on red blood cells [8].

Analytical, diagnostic and therapeutic context of ICAM4

  • Accordingly, by site-directed mutagenesis of 22 amino acid positions spread out on all faces of the ICAM-4 molecule, we identified four exposed residues, Leu(80), Trp(93), and Arg(97) on the CFG face and Trp(77) on the E-F loop of domain D1 that may contact LFA-1 as part of the binding site [15].
  • A rabbit antibody raised against the 15 N-terminal amino acids of the predicted protein reacted on immunoblots with authentic LW glycoprotein and in indirect agglutination test with all human erythrocytes except those from LW(a-b-) [4].
  • Study by Southern blot analysis indicated also that the LW locus is composed of a single gene that was not grossly rearranged in rare LW(a-b-) and Rhnull individuals deficient for LW antigens [9].
  • For example, the Lutheran, LW, and Ok glycoproteins are members of the immunoglobulin superfamily of receptors and signal transducers, the Rh proteins and related glycoproteins show homology to ammonium transporters, and the Kell glycoprotein resembles a family of endopeptidases [18].
  • Preliminary analyses by two-dimensional peptide mapping indicate that the 31,000 mol. wt polypeptide is identical to authentic Rh proteins, therefore raising the possibility that the Rh and LW antigens are associated in the membrane as a functional complex called Rh cluster [19].


  1. Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3 integrin. Hermand, P., Gane, P., Huet, M., Jallu, V., Kaplan, C., Sonneborn, H.H., Cartron, J.P., Bailly, P. J. Biol. Chem. (2003) [Pubmed]
  2. Linkage of the LW blood group locus with the complement C3 and Lutheran blood group loci. Sistonen, P. Ann. Hum. Genet. (1984) [Pubmed]
  3. Human Rhesus-associated glycoprotein mediates facilitated transport of NH(3) into red blood cells. Ripoche, P., Bertrand, O., Gane, P., Birkenmeier, C., Colin, Y., Cartron, J.P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. The LW blood group glycoprotein is homologous to intercellular adhesion molecules. Bailly, P., Hermand, P., Callebaut, I., Sonneborn, H.H., Khamlichi, S., Mornon, J.P., Cartron, J.P. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  5. Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrin CD11c/CD18: characterization of the binding sites on ICAM-4. Ihanus, E., Uotila, L.M., Toivanen, A., Varis, M., Gahmberg, C.G. Blood (2007) [Pubmed]
  6. Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus. Kammerer, S., Roth, R.B., Reneland, R., Marnellos, G., Hoyal, C.R., Markward, N.J., Ebner, F., Kiechle, M., Schwarz-Boeger, U., Griffiths, L.R., Ulbrich, C., Chrobok, K., Forster, G., Praetorius, G.M., Meyer, P., Rehbock, J., Cantor, C.R., Nelson, M.R., Braun, A. Cancer Res. (2004) [Pubmed]
  7. Intercellular adhesion molecule-4 binds alpha(4)beta(1) and alpha(V)-family integrins through novel integrin-binding mechanisms. Spring, F.A., Parsons, S.F., Ortlepp, S., Olsson, M.L., Sessions, R., Brady, R.L., Anstee, D.J. Blood (2001) [Pubmed]
  8. Characterization of the gene encoding the human LW blood group protein in LW+ and LW- phenotypes. Hermand, P., Le Pennec, P.Y., Rouger, P., Cartron, J.P., Bailly, P. Blood (1996) [Pubmed]
  9. Molecular basis and expression of the LWa/LWb blood group polymorphism. Hermand, P., Gane, P., Mattei, M.G., Sistonen, P., Cartron, J.P., Bailly, P. Blood (1995) [Pubmed]
  10. The red cell LW blood group protein is an intercellular adhesion molecule which binds to CD11/CD18 leukocyte integrins. Bailly, P., Tontti, E., Hermand, P., Cartron, J.P., Gahmberg, C.G. Eur. J. Immunol. (1995) [Pubmed]
  11. Biochemical aspects of the blood group Rh (rhesus) antigens. Anstee, D.J., Tanner, M.J. Baillieres Clin. Haematol. (1993) [Pubmed]
  12. Erythroid cell adhesion molecules Lutheran and LW in health and disease. Parsons, S.F., Spring, F.A., Chasis, J.A., Anstee, D.J. Baillière's best practice & research. Clinical haematology. (1999) [Pubmed]
  13. Characterization of ICAM-4 binding to the I domains of the CD11a/CD18 and CD11b/CD18 leukocyte integrins. Ihanus, E., Uotila, L., Toivanen, A., Stefanidakis, M., Bailly, P., Cartron, J.P., Gahmberg, C.G. Eur. J. Biochem. (2003) [Pubmed]
  14. Integrin receptor specificity for human red cell ICAM-4 ligand. Critical residues for alphaIIbeta3 binding. Hermand, P., Gane, P., Callebaut, I., Kieffer, N., Cartron, J.P., Bailly, P. Eur. J. Biochem. (2004) [Pubmed]
  15. Binding sites of leukocyte beta 2 integrins (LFA-1, Mac-1) on the human ICAM-4/LW blood group protein. Hermand, P., Huet, M., Callebaut, I., Gane, P., Ihanus, E., Gahmberg, C.G., Cartron, J.P., Bailly, P. J. Biol. Chem. (2000) [Pubmed]
  16. Advance in the Rh blood group system. Kajii, E. Nippon Hoigaku Zasshi (1998) [Pubmed]
  17. Defining the Rh blood group antigens. Biochemistry and molecular genetics. Cartron, J.P. Blood Rev. (1994) [Pubmed]
  18. Functional aspects of red cell antigens. Daniels, G. Blood Rev. (1999) [Pubmed]
  19. Properties of the blood group LW glycoprotein and preliminary comparison with Rh proteins. Bloy, C., Blanchard, D., Hermand, P., Kordowicz, M., Sonneborn, H.H., Cartron, J.P. Mol. Immunol. (1989) [Pubmed]
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