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integrins

Friday 11 July 2003

ITGs

Definition: Integrins are cell-surface receptors that mediate and coordinate cellular responses to the extracellular matrix.

Integrins are transmembrane heterodimeric glycoproteins, made up of α chains (ITGAs) and β chains (ITGBs), that are expressed on many cell types and bind to ligands on endothelial cells, other leukocytes, and the extracellular matrix.

Examples

- α4β7 integrin

The β2 integrins LFA-1 and Mac-1 (CD11a/CD18 and CD11b/CD18) bind to ICAM1, and the β1 integrins (such as VLA-4) bind VCAM1.

Cellular signalling pathways can regulate cell adhesion by altering the affinity and avidity of integrins for the extracellular matrix.

The integrin family (ITGs) includes cell surface receptors for extracellular matrix components as well as receptors involved in various aspects of leukocyte adhesion.

The integrins generally consist of alpha-beta heterodimeric transmembrane glycoproteins in which the alpha subunit (ITGAs) is noncovalently associated with the beta subunit (ITGBs).

Three major subfamilies of integrins have been defined, each containing a common beta subunit that can be associated with multiple alpha subunits.

Members

ITGAs ITGBs

The integrin superfamily consists of about 30 structurally homologous proteins that promote cell-cell or cell-matrix interactions.

The name of this family of proteins derives from the hypothesis that they coordinate (i.e., "integrate") signals from extracellular ligands with cytoskeleton-dependent motility, shape change, and phagocytic responses.

All integrins are heterodimeric cell surface proteins composed of two noncovalently linked polypeptide chains, α (ITGAs) and β (ITGBs).

The extracellular domains of the two chains bind to various ligands, including extracellular matrix glycoproteins, activated complement components, and proteins on the surfaces of other cells.

Several integrins bind to Arg-Gly-Asp (RGD) sequences in the fibronectin and vitronectin molecules. The cytoplasmic domains of the integrins interact with cytoskeletal components (including vinculin, talin, actin, α-actinin, and tropomyosin).

Three integrin subfamilies were originally defined on the basis of which of three β subunits were used to form the heterodimers. More recently, five additional β chains have been identified.

Beta1-integrins (ITGB1)

The β1-containing integrins (ITGB1) are also called VLA molecules, referring to "very late activation" molecules, because α1β1 and α2β1 were first shown to be expressed on T cells 2 to 4 weeks after repetitive stimulation in vitro. In fact, other VLA integrins are constitutively expressed on some leukocytes and rapidly induced on others.

The β1 integrins are also called CD49a-hCD29, CD49a-h referring to different α chains (α1-α8) and CD29 referring to the common β1 subunit. Most of the β1 integrins are widely expressed on leukocytes and other cells and mediate attachment of cells to extracellular matrices.

VLA-4 (α4β1) is expressed only on leukocytes and can mediate attachment of these cells to endothelium by interacting with vascular cell adhesion molecule-1 (VCAM1). VLA-4 is one of the principal surface proteins that mediate homing of lymphocytes to endothelium at peripheral sites of inflammation.

Beta2-integrins

The β2 integrins are also called CD11a-cCD18, or the leukocyte function-associated antigen-1 (LFA-1) family, CD11a-c referring to different α chains and CD18 to the common β2 subunit.

LFA-1 (CD11aCD18) plays an important role in the adhesion of lymphocytes and other leukocytes with other cells, such as antigen-presenting cells and vascular endothelium. Other members of the family include CD11bCD18 (Mac-1 or CR3) and CD11cCD18 (p150,95 or CR4), which mediate leukocyte attachment to endothelial cells and subsequent extravasation.

CD11bCD18 also functions as a fibrinogen receptor and as a complement receptor on phagocytic cells, binding particles opsonized with a by-product of complement activation called the inactivated C3b (iC3b) fragment.

The other integrins are expressed on platelets and other cell types, and bind to extracellular matrix proteins as well as proteins involved in coagulation.

Functions

Integrins are a large family of transmembrane receptors for extracellular matrix (ECM) molecules. They play a critical role in organ morphogenesis, physiology and pathology, as they can modulate and control different cell functions, including cell adhesion, cell shape, cell polarity, cell growth, cell differentiation and cell motility.

Integrins interact with ECM components via their extracellular domains, while their cytoplasmic domains play a pivotal role in mediating integrin-dependent cellular functions.

The integrin cytoplasmic tails interact with the cytoskeleton, signaling molecules and other cellular proteins, resulting in regulation of many biological functions.

Integrin signaling is bidirectional. ’Inside-out’ signals regulate integrin affinity for adhesive ligands, and ligand-dependent ’outside-in’ signals regulate cellular responses to adhesion. A key unresolved question is how integrins propagate signals across the plasma membrane.

Ligand binding to integrins causes clustering of the receptors in the cell membrane and formation of focal adhesion complexes. The cytoskeletal proteins that colocalize with integrins at the cell focal adhesion complex include talin (TKNs: TLN1 and TLN2), vinculin (VCL), and paxillin (PXN).

The integrin-cytoskeleton complexes function as activated receptors and trigger signal transduction pathways, which include the MAP kinase, PKC, and PI-3 kinase pathways.

Integrins bind both to matrix proteins such as fibronectin (FN1) and laminin (LAMs), mediating adhesiveness between cells and ECM, as well as to adhesive proteins in other cells, establishing cell-to-cell contacts.

Subtypes

- PS integrins

Features

- spatial pattern of integrins

Functional synopsis

- cell adhesion
- signaling
- morphogenesis

Pathology (integrin-dependent pathologies)

- leucocyte adhesion deficiency type 1 (LAD-1) : mutations of beta2-integrins (Deletion or reduced cell surface expression)

- Glanzmann thrombasthenia (GT) : mutations in alpahIIb and beta3-Integrins (deletions; point mutations in ligand binding site, stem and cytoplasmic tail)

- Glanzmann thrombasthenia : beta3-Integrins (Integrin locked in high affinity config (C560R))

- thrombosis : beta3-Integrins L33/P33 polymorphism; risc for thrombosis

- epidermolysis bullosa : beta6-integrins (Splicing defect in exon 12 (1856 + 1GtoT))

- epidermolysis bullosa 4-integrins missense and premature stop, cytoplasmic deletion

- Oral pemphigoid : alpha6-Integrins (Autoantibodies against alpha6 integrin)

- Congenital myopathy: alpha7-Integrins (Missense, internal insertions and deletions)

- Squamous cell carcinoma (SCC4): beta1-Integrins (Integrin activation, point mutation T188I in the ligand binding domain)

- ITGA6 and ITGB4 mutations in epidermolysis bullosa with pyloric atresia

Features

- cancer cell invasion
- cancer cell migration

References

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- De Arcangelis A, Georges-Labouesse E. Integrin and ECM functions: roles in vertebrate development. Trends Genet. 2000 Sep;16(9):389-95. PMID: 10973067

- Beauvais-Jouneau A, Thiery JP. Multiple roles for integrins during development. Biol Cell. 1997 Mar;89(1):5-11. PMID: 9297778