ICAM-1

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

Structure
ICAM-1 is a member of the is_associated_with::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 is_associated_with::glycosylation, and the protein’s extracellular domain is composed of multiple loops created by is_associated_with::disulfide bridges within the protein. The dominant secondary structure of the protein is the is_associated_with::beta sheet, leading researchers to hypothesize the presence of dimerization domains within ICAM-1.

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

Role in cell signaling
ICAM-1 (Intercellular Adhesion Molecule-1, CD54) is an endothelial- and is_associated_with::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 is_associated_with::rhinovirus. 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 is_associated_with::tight junctions forming the is_associated_with::blood-testis barrier, thus playing a major role in is_associated_with::spermatogenesis.

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 mac rophage adhesion ligand- 1 (Mac-1; ITGB2 / ITGAM), l eukocyte f unction associated a ntigen- 1 (LFA-1), and is_associated_with::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. ICAM-1 also became known for its affinity for is_associated_with::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.

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

ICAM-1 expressed by is_associated_with::respiratory epithelial cells is also the binding site for is_associated_with::rhinovirus, the causative agent of most is_associated_with::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 is_associated_with::CD11a,  EZR and is_associated_with::CD18.