Regulation of integrin activity and signalling

Abstract

The ability of cells to attach to each other and to the extracellular matrix is of pivotal significance for the formation of functional organs and for the distribution of cells in the body. Several molecular families of proteins are involved in adhesion, and recent work has substantially improved our understanding of their structures and functions. Also, these molecules are now being targeted in the fight against disease. However, less is known about how their activity is regulated. It is apparent that among the different classes of adhesion molecules, the integrin family of adhesion receptors are unique in the sense that they constitute a large group of widely distributed receptors, they are unusually complex and most importantly their activities are strictly regulated from the inside of the cell. The activity regulation is achieved by a complex interplay of cytoskeletal proteins, protein kinases, phosphatases, small G proteins and adaptor proteins. Obviously, we are only in the beginning of our understanding of how the integrins function, but already now fascinating details have become apparent. Here, we describe recent progress in the field, concentrating mainly on mechanistical and structural studies of integrin regulation. Due to the large number of articles dealing with integrins, we focus on what we think are the most exciting and rewarding directions of contemporary research on cell adhesion and integrins.

LFA-1 integrin antibodies inhibit leukocyte α4β1–mediated adhesion by intracellular signaling

“…However, integrin function is regulated by changes in phosphorylation and protein interactions in the cytoplasmic domains. [7][8][9][10] LFA-1 and a 4 b 1 mediate distinct steps in the adhesion cascade. a 4 b 1 mediates rolling and adhesion strengthening, whereas LFA-1 is needed for firm adhesion and migration.…”

Signaling Pathways Altered During the Metastatic Progression of Melanoma

“…In this regard, integrins have altered interactions with their microenvironment may give drastic consequences for cell fate as provide cell tend to lose their original adhesion, recognizing a different substrate and reconfigure it with characteristics that enable metastasize [21][22]. It is known that the increase and alteration of integrin expression is indicative of progression of melanoma [23]. Many integrins are found altered in metastatic melanoma (TABLE 1).…”

Integrin CD11c/CD18 α-Chain Phosphorylation Is Functionally Important

“…The importance of integrin ␤ chain phosphorylations in these activation events leading to integrin activation, actin cytoskeleton reorganization, cell adhesion, migration, and phagocytosis is well established, but far less is known about ␣-chain cytoplasmic events involved in integrin activity and functions (3,41). It has previously been shown that in neutrophils, monocytes, and mononuclear cells, CD11c is constitutively phosphorylated and the CD18 becomes phosphorylated upon activation (26,27).…”

“…Phosphorylation of Thr-758 on the ␤ 2 chain of CD11a/CD18 results in recruitment of 14-3-3 proteins followed by binding of the adaptor protein Tiam1 and activation of the small G protein Rac-1 (3,23,24). These events result in reorganization of the cytoskeleton and increased adhesion.…”

“…Other members include CD11a/CD18 (␣ L ␤ 2 , LFA-1), CD11b/CD18 (␣ M ␤ 2 , Mac-1), and CD11d/CD18 (␣ D ␤ 2 ). The leukocyte CD11/CD18 integrins are involved in various immunological functions, including cell adhesion, migration, and phagocytosis (2)(3)(4)(5)(6).…”