ICAM-1

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Intercellular adhesion molecule 1
PBB Protein ICAM1 image.jpg
PDB rendering based on 1d3e.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ICAM1 ; BB2; CD54; P3.58
External IDs OMIM147840 MGI96392 HomoloGene168 ChEMBL: 3070 GeneCards: ICAM1 Gene
RNA expression pattern
PBB GE ICAM1 202638 s at tn.png
PBB GE ICAM1 207194 s at tn.png
PBB GE ICAM1 202637 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3383 15894
Ensembl ENSG00000090339 ENSMUSG00000037405
UniProt P05362 P13597
RefSeq (mRNA) NM_000201 NM_010493
RefSeq (protein) NP_000192 NP_034623
Location (UCSC) Chr 19:
10.38 – 10.4 Mb
Chr 9:
21.02 – 21.03 Mb
PubMed search [1] [2]

ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ICAM1 gene.[1][2] This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor.[3]

Structure[edit]

ICAM-1 is a member of the immunoglobulin superfamily, the superfamily of proteins including antibodies and T-cell receptors. ICAM-1 is a transmembrane protein possessing an amino-terminus extracellular domain, a single transmembrane domain, and a carboxy-terminus cytoplasmic domain. The structure of ICAM-1 is characterized by heavy glycosylation, and the protein’s extracellular domain is composed of multiple loops created by disulfide bridges within the protein. The dominant secondary structure of the protein is the beta sheet, leading researchers to hypothesize the presence of dimerization domains within ICAM-1.[4]

Function[edit]

The protein encoded by this gene is a type of intercellular adhesion molecule continuously present in low concentrations in the membranes of leukocytes and endothelial cells. Upon cytokine stimulation, the concentrations greatly increase. ICAM-1 can be induced by interleukin-1 (IL-1) and tumor necrosis factor (TNF) and is expressed by the vascular endothelium, macrophages, and lymphocytes. ICAM-1 is a ligand for LFA-1 (integrin), a receptor found on leukocytes.[5] When activated, leukocytes bind to endothelial cells via ICAM-1/LFA-1 and then transmigrate into tissues.[6]

Role in cell signaling[edit]

ICAM-1 (Intercellular Adhesion Molecule-1, CD54) is an endothelial- and leukocyte-associated transmembrane protein long known for its importance in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. More recently, ICAM-1 has been characterized as a site for the cellular entry of human rhinovirus.[7] Because of these associations with immune responses, it has been hypothesized that ICAM-1 could function in signal transduction. ICAM-1 ligation produces proinflammatory effects such as inflammatory leukocyte recruitment by signaling through cascades involving a number of kinases, including the kinase p56lyn.

Other functions[edit]

ICAM-1 and soluble ICAM-1 have antagonistic effects on the tight junctions forming the blood-testis barrier, thus playing a major role in spermatogenesis.[8]

The presence of heavy glycosylation and other structural characteristics of ICAM-1 lend the protein binding sites for numerous ligands. ICAM-1 possesses binding sites for a number of immune-associated ligands. Notably, ICAM-1 binds to macrophage adhesion ligand-1 (Mac-1; ITGB2 / ITGAM), leukocyte function associated antigen-1 (LFA-1), and fibrinogen. These three proteins are generally expressed on endothelial cells and leukocytes, and they bind to ICAM-1 to facilitate transmigration of leukocytes across vascular endothelia in processes such as extravasation and the inflammatory response. As a result of these binding characteristics, ICAM-1 has classically been assigned the function of intercellular adhesion.

Researchers began to question the role of ICAM-1 as a simple adhesion molecule upon discovering that ICAM-1 serves as the binding site for entry of the major group of human rhinovirus (HRV) into various cell types.[4] ICAM-1 also became known for its affinity for plasmodium falciparum-infected erythrocytes (PFIE), providing more of a role for ICAM-1 in infectious disease.

With the roles of ICAM-1 in cell-cell adhesion, extravasation, and infection more fully understood, a potential role for ICAM-1 in signal transduction was hypothesized. Most of the work involving ICAM-1 in recent years has focused on this central question as well as related questions. Researchers reasoned that, should ICAM-1 signal transduction prove to occur, it would be necessary to identify the mechanism of that signaling, the conditions and environment in which the signaling would occur, and the biological endpoints of any signaling cascades involved. Beyond its classically described functions as an adhesion and viral entry molecule, ICAM-1 has now been characterized convincingly as possessing a role in signal transduction. Furthermore, the signal-transducing functions of ICAM-1 seem to be associated primarily with proinflammatory pathways. In particular, ICAM-1 signaling seems to produce a recruitment of inflammatory immune cells such as macrophages and granulocytes.[9]

ICAM-1 may also participate in a positive-feedback loop and compete with ICAM-2 to maintain a proinflammatory environment conducive to leukocyte endothelial transmigration. At both the mRNA and protein levels of expression, ICAM-1 ligation was found to upregulate ICAM-1’s own expression in a positive-feedback loop. In addition, the expression of RANTES mRNA and protein was also found to be upregulated by ICAM-1 ligation. RANTES, or Regulated upon Activation Normal T-cell Expressed and Secreted, is a cytokine that is an inflammatory mediator chemotactic for a variety of inflammatory immune cells such as granulocytes and macrophages.[10] However, much work remains to be done in fully characterizing the signaling of ICAM-1. The relationship between ICAM-1 and ICAM-2 signaling environments has not been established beyond mere correlation; a study linking ICAM signaling to actual modulation of an inflammatory environment in vivo has yet to be conducted. The reticular nature of signaling cascades necessitates that the downstream effectors of ICAM-1 mediated signaling through various kinases including p56lyn, Raf-1, and the MAPKs are largely unknown. A more thorough study of the cross-talk between these signaling molecules may shed further light onto the biological endpoints produced by ICAM-1 ligation and signal transduction.

Clinical significance[edit]

ICAM-1 has been implicated in subarachnoid hemorrhage (SAH). Levels of ICAM-1 are shown to be significantly elevated in patients with SAH over control subjects in many studies.[11][12] While ICAM-1 has not been shown to be directly correlated with cerebral vasospasm, a secondary symptom that affects 70% of SAH patients, treatment with anti-ICAM-1 reduced the severity of vasospasm.

ICAM-1 expressed by respiratory epithelial cells is also the binding site for rhinovirus, the causative agent of most common colds.

ICAM-1 has an important role in ocular allergies recruiting pro-inflammatory lymphocytes and mast cells promoting a type I hypersensitivity reaction.

Interactions[edit]

ICAM-1 has been shown to interact with CD11a,[13][14][15] EZR[16] and CD18.[13][17][18]

References[edit]

  1. ^ Carlson M, Nakamura Y, Payson R, O'Connell P, Leppert M, Lathrop GM, Lalouel JM, White R (May 1988). "Isolation and mapping of a polymorphic DNA sequence (pMCT108.2) on chromosome 18 D18S24". Nucleic Acids Res. 16 (9): 4188. doi:10.1093/nar/16.9.4188. PMC 336612. PMID 2453850. 
  2. ^ Katz FE, Parkar M, Stanley K, Murray LJ, Clark EA, Greaves MF (January 1985). "Chromosome mapping of cell membrane antigens expressed on activated B cells". Eur. J. Immunol. 15 (1): 103–6. doi:10.1002/eji.1830150121. PMID 3871395. 
  3. ^ "Entrez Gene: intercellular adhesion molecule 1". 
  4. ^ a b Bella J, Kolatkar PR, Marlor CW, Greve JM, Rossmann MG (April 1998). "The structure of the two amino-terminal domains of human ICAM-1 suggests how it functions as a rhinovirus receptor and as an LFA-1 integrin ligand". Proc. Natl. Acad. Sci. U.S.A. 95 (8): 4140–5. doi:10.1073/pnas.95.8.4140. PMC 22455. PMID 9539703. 
  5. ^ Rothlein, R. D. (Aug 1986). "A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1". Journal of Immunology 137 (4): 1270–1274. ISSN 0022-1767. PMID 3525675.  |first2= missing |last2= in Authors list (help); |first3= missing |last3= in Authors list (help); |first4= missing |last4= in Authors list (help) edit
  6. ^ Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW (July 2005). "ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-α-activated vascular endothelium under flow". Blood 106 (2): 584–92. doi:10.1182/blood-2004-12-4942. PMC 1635241. PMID 15811956. 
  7. ^ Abraham G, Colonno RJ (August 1984). "Many rhinovirus serotypes share the same cellular receptor". J. Virol. 51 (2): 340–5. PMC 254443. PMID 6086949. 
  8. ^ Xiao, X.; Mruk, D. D.; Cheng, C. Y. (2013). "Intercellular adhesion molecules (ICAMs) and spermatogenesis". Human Reproduction Update 19 (2): 167–186. doi:10.1093/humupd/dms049. PMC 3576004. PMID 23287428.  edit
  9. ^ Etienne-Manneville S, Chaverot N, Strosberg AD, Couraud PO (July 1999). "ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion". J. Immunol. 163 (2): 668–74. PMID 10395656. 
  10. ^ Blaber R, Stylianou E, Clayton A, Steadman R (January 2003). "Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts". J. Am. Soc. Nephrol. 14 (1): 116–27. doi:10.1097/01.ASN.0000040595.35207.62. PMID 12506144. 
  11. ^ Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS (October 1998). "Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage". J. Neurosurg. 89 (4): 559–67. doi:10.3171/jns.1998.89.4.0559. PMID 9761049. 
  12. ^ Frijns CJ, Kappelle LJ (August 2002). "Inflammatory cell adhesion molecules in ischemic cerebrovascular disease". Stroke 33 (8): 2115–22. doi:10.1161/01.STR.0000021902.33129.69. PMID 12154274. 
  13. ^ a b Lu, C; Takagi J, Springer T A (May 2001). "Association of the membrane proximal regions of the alpha and beta subunit cytoplasmic domains constrains an integrin in the inactive state". J. Biol. Chem. (United States) 276 (18): 14642–8. doi:10.1074/jbc.M100600200. ISSN 0021-9258. PMID 11279101. 
  14. ^ Shimaoka, Motomu; Xiao Tsan, Liu Jin-Huan, Yang Yuting, Dong Yicheng, Jun Chang-Duk, McCormack Alison, Zhang Rongguang, Joachimiak Andrzej, Takagi Junichi, Wang Jia-Huai, Springer Timothy A (Jan 2003). "Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation". Cell (United States) 112 (1): 99–111. doi:10.1016/S0092-8674(02)01257-6. ISSN 0092-8674. PMID 12526797. 
  15. ^ Yusuf-Makagiansar, H; Makagiansar I T; Hu Y; Siahaan T J (Dec 2001). "Synergistic inhibitory activity of alpha- and beta-LFA-1 peptides on LFA-1/ICAM-1 interaction". Peptides (United States) 22 (12): 1955–62. doi:10.1016/S0196-9781(01)00546-0. ISSN 0196-9781. PMID 11786177. 
  16. ^ Heiska, L; Alfthan K; Grönholm M; Vilja P; Vaheri A; Carpén O (Aug 1998). "Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate". J. Biol. Chem. (UNITED STATES) 273 (34): 21893–900. doi:10.1074/jbc.273.34.21893. ISSN 0021-9258. PMID 9705328. 
  17. ^ Kotovuori, A; Pessa-Morikawa T; Kotovuori P; Nortamo P; Gahmberg C G (Jun 1999). "ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity". J. Immunol. (UNITED STATES) 162 (11): 6613–20. ISSN 0022-1767. PMID 10352278. 
  18. ^ Huang, C; Springer T A (Aug 1995). "A binding interface on the I domain of lymphocyte function-associated antigen-1 (LFA-1) required for specific interaction with intercellular adhesion molecule 1 (ICAM-1)". J. Biol. Chem. (UNITED STATES) 270 (32): 19008–16. doi:10.1074/jbc.270.32.19008. ISSN 0021-9258. PMID 7642561. 

Further reading[edit]

External links[edit]