ICAM-1

Intercellular adhesion molecule 1
PDB rendering based on 1d3e.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1D3E​, 1D3I​, 1D3L​, 1IAM​, 1IC1​, 1IJ4​, 1MQ8​, 1P53​, 1Z7Z​, 2OZ4​, 3TCX​
Identifiers
Symbols	ICAM1 ; BB2; CD54; P3.58
External IDs	OMIM: 147840 MGI: 96392 HomoloGene: 168 ChEMBL: 3070 GeneCards: ICAM1 Gene
Gene ontology Molecular function • virus receptor activity • receptor activity • transmembrane signaling receptor activity • integrin binding • protein binding Cellular component • immunological synapse • extracellular space • plasma membrane • integral component of plasma membrane • focal adhesion • external side of plasma membrane • cell surface • membrane • membrane raft • extracellular exosome Biological process • ovarian follicle development • regulation of leukocyte mediated cytotoxicity • response to amphetamine • T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell • acute inflammatory response to antigenic stimulus • T cell antigen processing and presentation • positive regulation of cellular extravasation • cell adhesion • heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules • leukocyte cell-cell adhesion • cell aging • sensory perception of sound • regulation of cell shape • response to ionizing radiation • response to sulfur dioxide • response to organic cyclic compound • cytokine-mediated signaling pathway • membrane to membrane docking • regulation of cell adhesion • extracellular matrix organization • positive regulation of actin filament polymerization • cellular response to nutrient levels • cell adhesion mediated by integrin • response to gonadotropin • response to drug • response to amino acid • positive regulation of GTPase activity • adhesion of symbiont to host • positive regulation of nitric oxide biosynthetic process • response to ethanol • positive regulation of vasoconstriction • response to copper ion • viral entry into host cell • receptor-mediated virion attachment to host cell • positive regulation of peptidyl-tyrosine phosphorylation • regulation of immune response • leukocyte migration • positive regulation of NF-kappaB transcription factor activity • negative regulation of calcium ion transport • interferon-gamma-mediated signaling pathway • establishment of endothelial barrier • positive regulation of ERK1 and ERK2 cascade • cellular response to lipopolysaccharide • cellular response to alkaloid • cellular response to glucose stimulus • cellular response to interleukin-1 • cellular response to tumor necrosis factor • cellular response to hypoxia • establishment of Sertoli cell barrier • regulation of ruffle assembly • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • negative regulation of endothelial cell apoptotic process Sources: Amigo / QuickGO
RNA expression pattern
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: 10.27 – 10.29 Mb	Chr 9: 21.02 – 21.03 Mb
PubMed search

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

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

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] LFA-1 has also been found in a soluble form,^[7] which seems to bind and block ICAM-1.^[8]

Role in cell signaling

ICAM-1 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.^[9] 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

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.^[10]

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.^[11]

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.^[12] 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

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.^[13][14] 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

ICAM-1 has been shown to interact with CD11a,^[15][16][17] EZR^[18] and CD18.^[15][19][20]

References

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 Research 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 (Jan 1985). "Chromosome mapping of cell membrane antigens expressed on activated B cells". European Journal of Immunology 15 (1): 103–6. doi:10.1002/eji.1830150121. PMID 3871395.
3. "Entrez Gene: intercellular adhesion molecule 1".
4. Bella J, Kolatkar PR, Marlor CW, Greve JM, Rossmann MG (Apr 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". Proceedings of the National Academy of Sciences of the United States of America 95 (8): 4140–5. doi:10.1073/pnas.95.8.4140. PMC 22455. PMID 9539703.
5. Rothlein R, Dustin ML, Marlin SD, Springer TA (Aug 1986). "A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1". Journal of Immunology 137 (4): 1270–4. PMID 3525675.
6. Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW (Jul 2005). "ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow". Blood 106 (2): 584–92. doi:10.1182/blood-2004-12-4942. PMC 1635241. PMID 15811956.
7. Gjelstrup, L. C.; Boesen, T.; Kragstrup, T. W.; Jorgensen, A.; Klein, N. J.; Thiel, S.; Deleuran, B. W.; Vorup-Jensen, T. (8 September 2010). "Shedding of Large Functionally Active CD11/CD18 Integrin Complexes from Leukocyte Membranes during Synovial Inflammation Distinguishes Three Types of Arthritis through Differential Epitope Exposure". The Journal of Immunology 185 (7): 4154–4168. doi:10.4049/jimmunol.1000952.
8. Kragstrup, Tue W; Jalilian, Babak; Hvid, Malene; Kjærgaard, Anders; Østgård, René; Schiøttz-Christensen, Berit; Jurik, Anne G; Robinson, William H; Vorup-Jensen, Thomas; Deleuran, Bent (2014). "Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis". Arthritis Research & Therapy 16 (1): R42. doi:10.1186/ar4471.
9. Abraham G, Colonno RJ (Aug 1984). "Many rhinovirus serotypes share the same cellular receptor". Journal of Virology 51 (2): 340–5. PMC 254443. PMID 6086949.
10. Xiao X, Mruk DD, Cheng CY (2013). "Intercellular adhesion molecules (ICAMs) and spermatogenesis". Human Reproduction Update 19 (2): 167–86. doi:10.1093/humupd/dms049. PMC 3576004. PMID 23287428.
11. Etienne-Manneville S, Chaverot N, Strosberg AD, Couraud PO (Jul 1999). "ICAM-1-coupled signaling pathways in astrocytes converge to cyclic AMP response element-binding protein phosphorylation and TNF-alpha secretion". Journal of Immunology 163 (2): 668–74. PMID 10395656.
12. Blaber R, Stylianou E, Clayton A, Steadman R (Jan 2003). "Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts". Journal of the American Society of Nephrology 14 (1): 116–27. doi:10.1097/01.ASN.0000040595.35207.62. PMID 12506144.
13. Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS (Oct 1998). "Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage". Journal of Neurosurgery 89 (4): 559–67. doi:10.3171/jns.1998.89.4.0559. PMID 9761049.
14. Frijns CJ, Kappelle LJ (Aug 2002). "Inflammatory cell adhesion molecules in ischemic cerebrovascular disease". Stroke; A Journal of Cerebral Circulation 33 (8): 2115–22. doi:10.1161/01.STR.0000021902.33129.69. PMID 12154274.
15. Lu C, Takagi J, Springer TA (May 2001). "Association of the membrane proximal regions of the alpha and beta subunit cytoplasmic domains constrains an integrin in the inactive state". The Journal of Biological Chemistry 276 (18): 14642–8. doi:10.1074/jbc.M100600200. PMID 11279101.
16. Shimaoka M, Xiao T, Liu JH, Yang Y, Dong Y, Jun CD, McCormack A, Zhang R, Joachimiak A, Takagi J, Wang JH, Springer TA (Jan 2003). "Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation". Cell 112 (1): 99–111. doi:10.1016/S0092-8674(02)01257-6. PMID 12526797.
17. Yusuf-Makagiansar H, Makagiansar IT, Hu Y, Siahaan TJ (Dec 2001). "Synergistic inhibitory activity of alpha- and beta-LFA-1 peptides on LFA-1/ICAM-1 interaction". Peptides 22 (12): 1955–62. doi:10.1016/S0196-9781(01)00546-0. PMID 11786177.
18. 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". The Journal of Biological Chemistry 273 (34): 21893–900. doi:10.1074/jbc.273.34.21893. PMID 9705328.
19. Kotovuori A, Pessa-Morikawa T, Kotovuori P, Nortamo P, Gahmberg CG (Jun 1999). "ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity". Journal of Immunology 162 (11): 6613–20. PMID 10352278.
20. Huang C, Springer TA (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)". The Journal of Biological Chemistry 270 (32): 19008–16. doi:10.1074/jbc.270.32.19008. PMID 7642561.

Further reading

• Wahl SM, et al. (Sep 2000). "Permissive factors for HIV-1 infection of macrophages". Journal of Leukocyte Biology 68 (3): 303–10. PMID 10985244.
• Yonekawa K, Harlan JM (Feb 2005). "Targeting leukocyte integrins in human diseases". Journal of Leukocyte Biology 77 (2): 129–40. doi:10.1189/jlb.0804460. PMID 15548573.
• Chakravorty SJ, Craig A (Jan 2005). "The role of ICAM-1 in Plasmodium falciparum cytoadherence". European Journal of Cell Biology 84 (1): 15–27. doi:10.1016/j.ejcb.2004.09.002. PMID 15724813.
• Lebedeva T, Dustin ML, Sykulev Y (Jun 2005). "ICAM-1 co-stimulates target cells to facilitate antigen presentation". Current Opinion in Immunology 17 (3): 251–8. doi:10.1016/j.coi.2005.04.008. PMID 15886114.
• Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW (Jul 2005). "ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-alpha-activated vascular endothelium under flow". Blood 106 (2): 584–92. doi:10.1182/blood-2004-12-4942. PMC 1635241. PMID 15811956.

External links

• Intercellular Adhesion Molecule-1 at the US National Library of Medicine Medical Subject Headings (MeSH)