Adhesion Molecules II

First printed in R&D Systems' 2001 Catalog.

Contents

Introduction

Cell surface adhesion molecules play vital roles in numerous cellular processes. Some of these include: cell growth, differentiation, embryogenesis, immune cell transmigration and response, and cancer metastasis. Adhesion molecules are also capable of transmitting information from the extracellular matrix to the cell. There are four major families of cell adhesion molecules. These are the immunoglobulin (Ig) superfamily cell adhesion molecules (CAMs), integrins, cadherins, and selectins.1-4

Ig superfamily CAMs

The Ig superfamily CAMs are calcium-independent transmembrane glycoproteins.2-4 Members of the Ig superfamily include the intercellular adhesion molecules (ICAMs), vascular-cell adhesion molecule (VCAM-1), platelet-endothelial-cell adhesion molecule (PECAM-1), and neural-cell adhesion molecule (NCAM). Each Ig superfamily CAM has an extracellular domain, which contains several Ig-like intrachain disulfide-bonded loops with conserved cysteine residues, a transmembrane domain, and an intracellular domain that interacts with the cytoskeleton. Typically, they bind integrins or other Ig superfamily CAMs. The neuronal CAMs have been implicated in neuronal patterning. Endothelial CAMs play an important role in immune response and inflammation.

Integrins

Integrins are non-covalently linked heterodimers of alpha and beta subunits.1, 2, 4-8 They are transmembrane proteins that are constitutively expressed, but require activation in order to bind their ligand. To date, 15 a subunits and 8 ß subunits have been identified. These can combine in various ways to form different types of integrin receptors. The associations between α and ß subunits are restricted (see Table 1 below for major integrin pairings). For example, not every a and ß combination will be observed. In most cases, one ß subunit combines with several different a subunits to form a subfamily of integrin receptors.1, 4, 6, 7

Integrins exhibit both “outside-in” and “inside-out” signaling properties.1, 4, 5, 9, 10 An example of “inside-out” signaling occurs when a cell stimulus, for example, triggering of the TCR/CD3 complex on an immune cell, activates the integrin receptor. This can activate it to bind its ligand. “Inside-out” signaling may also down-regulate integrin activation. “Outside-in” signaling occurs after the integrin receptor binds its ligand and a signal is transmitted from the integrin receptor into the cell. Integrins appear to have three activation states: basal avidity, low avidity, and high avidity. Additionally, cells will alter their expression of various integrin receptors depending on activation state, maturity, or lineage. Integrins are capable of binding divalent cations such as calcium, magnesium, and manganese. Magnesium and manganese alone are capable of activating integrins.

Cadherins

The cadherins are calcium-dependent adhesion molecules.2, 4, 11, 12 The three most common cadherins are neural (N)-cadherin, placental (P)-cadherin, and epithelial (E)-cadherin. All three belong to the classical cadherin subfamily. There are also desmosomal cadherins and proto-cadherins. Cadherins are intimately involved in embryonic development and tissue organization. They exhibit homophilic adhesion. The extracellular domain consists of several cadherin repeats, each is capable of binding a calcium ion. When calcium is bound, the extracellular domain has a rigid, rod-like structure. Following the transmembrane domain, the intracellular domain is highly conserved. The intracellular domain is capable of binding the a, ß, and ? catenins. The adhesive properties of the cadherins have been shown to be dependent upon the ability of the intracellular domain to interact with cytoplasmic proteins such as the catenins.

Selectins

The selectins are a family of divalent cation dependent glycoproteins.1, 2, 4, 8 They are carbohydrate-binding proteins, binding fucosylated carbohydrates, especially, sialylated Lewisx, and mucins.1, 2, 4, 8, 13, 14 The three family members include: Endothelial (E)-selectin, leukocyte (L)-selectin, and platelet (P)-selectin. The extracellular domain of each consists of a carbohydrate recognition motif, an epidermal growth factor (EGF)-like motif, and varying numbers of a short repeated domain related to complement-regulatory proteins (CRP).

Following the transmembrane region, each has a short cytoplasmic domain. The selectins play an important role in the initial steps of leukocyte trafficking. One selectin receptor, P-selectin glycoprotein ligand-1 (PSGL-1), requires specific carbohydrate decoration for full bioactivity.

CAMs are critical to numerous cellular processes and responses. Additionally, they also play a role in various disease states. Transendothelial migration of leukocytes is an example of one of the many roles of adhesion molecules.1, 4, 8, 15 This type of leukocyte trafficking consists of four distinct steps. The first is rolling of the circulating leukocyte along endothelial cells (i.e., leukocyte rolling on a blood vessel wall). This step is selectin-mediated. The second step involves the triggering or activation of cell surface adhesion molecules, namely, the integrins. This can be accomplished through contact with specific ECM proteins, inflammatory cytokines, or chemokines. The third step involves firm adhesion; the leukocyte firmly attaches to an endothelial cell. This involves arrest of the rolling process and spreading over the endothelial surface, typically a vessel wall. The integrins and their ligands play crucial roles in this step. The fourth step is transmigration of the leukocyte through adjacent endothelial cells in a process called diapedesis. This allows the leukocyte to enter the subendothelial space. PECAM-1 is a crucial player in this step. Transendothelial migration demonstrates cooperativity between leukocyte and endothelial cell adhesion molecules. An extremely complicated process can be broken down into distinct steps, each controlled by specific cell adhesion molecules.

Tumorigenesis is another process that involves cell adhesion molecules.2, 4, 16-20 For successful tumorigenesis, there must be changes in cellular adhesivity which facilitate the disruption of normal tissue architecture. Additionally, angiogenesis must occur to provide the growing tumor with a blood supply. During metastasis, cells must be able to detach from the primary tumor, enter the blood stream through attachment to a blood vessel wall, travel through the bloodstream, and attach to a vessel wall at a secondary site in order to establish a new tumor.

Defects in cell adhesion molecules are also associated with disease states. For example, leukocyte adhesion deficiency (LAD) syndrome is associated with adhesion cascade defects. LAD I is associated with mutations in the ß2 integrin. There are two forms that have been identified. The first is quite severe, with no LFA-1 (aLß2) expression. Patients with the second form express low levels of ß2 (i.e., about 2 - 5% of normal levels). Patients with the first form of LAD I usually die within a few years of birth unless they receive a bone marrow transplantation. Patients expressing the second form of LAD I have a moderate phenotype, but experience numerous types of infections. LAD II results from a defect in the selectins. It is extremely rare and less severe than LAD I. However, patients also exhibit severe mental and growth retardation believed to be due to a generalized defect in fucose metabolism.8

CAMs also play a role in establishment of the blood-brain barrier and facilitate its penetration by immune cells. Selectins and integrins are the most important cell adhesion molecules in this process.21 CAMs have also been used by pathogenic microorganisms to evade the immune system.22

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