Integrin

An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. It plays a role in the attachment of a cell to the extracellular matrix (ECM) (especially in growth cone axon guidance) and in signal transduction from the ECM to the cell. There are many different types of integrin and many cells have multiple types on their surface. Integrins are of vital importance to most multicellular organisms from humans to sponges.

Mutations in the genes encoding for integrin can be found in certain types of cancer, for instance breast cancer. A failure of integrin to anchor a cell to the ECM can play a role in the metastasis of certain cancer cells.

Other types of protein that play a role in cell-cell/cell-matrix interaction and communication are cadherins, NCAMs and selectins.

Structure

Integrins are obligate heterodimers containing two distinct chains, termed the α (alpha) and β (beta) subunits. About 18 α and 8 β subunits have been characterized. In addition, variants of some of the subunits are formed by differential splicing, for example 4 variants of the beta-1 subunit exist. Through different combinations of these alpha and beta subunits, some 24 unique integrins are generated. Integrin subunits penetrate the plasma membrane, and in general have very short cytoplasmic domains of about 40-70 amino acids, with the exception of the beta-4 subunit which has a cytoplasmic domain of 1088 amino acids. Outside the cell plasma membrane, the chains lie close together along a length of about 23 nm, the final 5 nm of each chain form a ligand-binding region for the ECM. The molecular mass of the integrin subunits can vary from 90 Kda to 160Kda. subunits have four cysteine-rich repeated sequences. a subunits bind several divalent cations. X-ray crystal structure has been obtained for the complete extracellular regions of one integrin, and this shows the molecule to be folded into an inverted V-shape which brings the ligand-binding sites close to the cell membrane. The current hypothesis, is that integrin function involves changes in shape to move the ligand binding site into a more accessible position away from the cell surface, and this shape change also triggers intracellular signalling.

Function

Two main functions of integrins are:

- Attachment of the cell to the ECM.
- Signal transduction from the ECM to the cell.

However, they are also involved in a wide range of other biological activities. These include: binding of viruses, including adenovirus, Echo viruses, Hanta viruses, foot and mouth disease viruses, to cells; immune patrolling. Cell migration.

Attachment of cell to the ECM

Integrins couple the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is mainly decided by which α and β subunits the integrin is made of. Among the ligands of integrins are fibronectin, collagen, and laminin. The connection between the cell and the ECM enables the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny.

The connections between integrin and the ligands in the ECM and the microfilaments inside the cell are indirect: they are linked via scaffolding proteins like talin, paxillin and alpha-actinin. These act by regulating kinases like FAK (focal adhesion kinase)and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as Crk.

Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF, EGF and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart, both literally and figuratively, of cellular biological processes.

Recent studies have focused on the role of ECM to influence the cellular microenvironment and resulting cellular function. Not only are integrins used, but recent advances in synthetic ECM analogues - such as synthetic peptide nanofiber scaffolds - are allowing well-defined blank scaffolds to serve as the basis for carefully controlled microenvironments for these studies.

Signal transduction

Integrins play an important role in cell signaling. Connection with ECM molecules can cause a signal to be relayed into the cell through protein kinases that are connected with the intracellular end of the integrin molecule.

The signals the cell receives through the integrin can have relation to:

- cell growth
- cell division
- cell survival
- cellular differentiation
- apoptosis (programmed cell death) .

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