integrins

インテグリン

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/27 19:17:37」(JST)

wiki en

[Wiki en表示]

Integrin alphavbeta3 extracellular domains
Structure of the extracellular segment of integrin alpha Vbeta3.
Identifiers
Symbol	Integrin_alphaVbeta3
Pfam	PF08441
Pfam clan	CL0159
InterPro	IPR013649
SCOP	1jv2
SUPERFAMILY	1jv2
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Integrin alpha cytoplasmic region
Structure of chaperone protein PAPD.
Identifiers
Symbol	Integrin_alpha
Pfam	PF00357
InterPro	IPR000413
PROSITE	PDOC00215
SCOP	1dpk
SUPERFAMILY	1dpk
OPM superfamily	197
OPM protein	2knc
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Integrin, beta chain
Identifiers
Symbol	Integrin_beta
Pfam	PF00362
InterPro	IPR002369
SMART	SM00187
PROSITE	PDOC00216
SCOP	1jv2
SUPERFAMILY	1jv2
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Integrin beta 7 cytoplasmic domain: complex with filamin
crystal structure of the filamin a repeat 21 complexed with the integrin beta7 cytoplasmic tail peptide
Identifiers
Symbol	Integrin_b_cyt
Pfam	PF08725
InterPro	IPR014836
SCOP	1m8O
SUPERFAMILY	1m8O
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Integrins are transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions. When triggered, integrins in turn trigger chemical pathways to the interior (signal transduction), such as the chemical composition and mechanical status of the ECM, which results in a response (activation of transcription) such as regulation of the cell cycle, cell shape, and/or motility; or new receptors being added to the cell membrane. This allows rapid and flexible responses to events at the cell surface, for example to signal platelets to initiate an interaction with coagulation factors.

There are several types of integrins, and a cell may have several types on its surface. Integrins are found in all metazoa.

Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen, and laminin.

Structure

Integrins have two different chains, the α (alpha) and β (beta) subunits, and are called obligate heterodimers. In mammals, there are eighteen α and eight β subunits, in Drosophila five α and two β subunits, and in Caenorhabditis nematodes two α subunits and one β subunit. The α and β subunits each penetrate the plasma membrane and possess small cytoplasmic domains.

alpha

gene	protein	synonyms are
ITGA1	CD49a	VLA1
ITGA2	CD49b	VLA2
ITGA3	CD49c	VLA3
ITGA4	CD49d	VLA4
ITGA5	CD49e	VLA5
ITGA6	CD49f	VLA6
ITGA7	ITGA7	FLJ25220
ITGA8	ITGA8
ITGA9	ITGA9	RLC
ITGA10	ITGA10
ITGA11	ITGA11	HsT18964
ITGAD	CD11D	FLJ39841
ITGAE	CD103	HUMINAE
ITGAL	CD11a	LFA1A
ITGAM	CD11b	MAC-1
ITGAV	CD51	VNRA, MSK8
ITGA2B	CD41	GPIIb
ITGAX	CD11c

beta

gene	protein	synonyms
ITGB1	CD29	FNRB, MSK12, MDF2
ITGB2	CD18	LFA-1, MAC-1, MFI7
ITGB3	CD61	GP3A, GPIIIa
ITGB4	CD104
ITGB5	ITGB5	FLJ26658
ITGB6	ITGB6
ITGB7	ITGB7
ITGB8	ITGB8

Variants of some of the subunits are formed by differential RNA splicing; for example, four variants of the beta-1 subunit exist. Through different combinations of the α and β subunits, around 24 unique integrins are generated.

Integrin subunits span the cell membrane and have short cytoplasmic domains of 40–70 amino acids. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of about 23 nm; the final 5 nm N-termini of each chain forms a ligand-binding region for the ECM. They have been compared to lobster claws, although the don't actually "pinch" their ligand, they chemically interact with it at the insides of the "tips" of their "pinchers".

The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. Beta subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations. The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.

There are various ways of categorizing the integrins. For example, a subset of the α chains has an additional structural element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein von Willebrand factor; it is also termed the α-I domain). Integrins carrying this domain either bind to collagens (e.g. integrins α1 β1, and α2 β1), or act as cell-cell adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but this A-domain is found on the β subunit.

In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-letter amino acid code).

Structure

Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging: membrane proteins are classically difficult to purify, and integrins are also large, complex and linked to many sugar trees ("highly glycosylated"). Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, and even data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains.

Despite these wide-ranging efforts, the X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3, was a surprise. It showed the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.

The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work. It appears that the integrin transmembrane helices are tilted (see "Activation" below), which hints that the extracellular chains may also not be orthogonal with respect to the membrane surface.

Although the crystal structure changed surprisingly little after binding to cilengitide, 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 signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibodies that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look on the structure is still unknown.

Activation

When released into the cell membrane, newly synthesized integrin dimers are speculated to be found in the same "bent" conformation revealed by the structural studies described above. One school of thought claims that this bent form prevents them from interacting with their ligands, although bent forms can predominate in high-resolution EM structures of integrin bound to an ECM ligand. Therefore, at least in biochemical experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to the ECM. In cells, the priming is accomplished by a protein talin, which binds to the β tail of the integrin dimer and changes its conformation. The α and β integrin chains are both class-I transmembrane proteins: they pass the plasma membrane as single transmembrane alpha-helices. Unfortunately, the helices are too long, and recent studies suggest that, for integrin gpIIbIIIa, they are tilted with respect both to one another and to the plane of the membrane. Talin binding alters the angle of tilt of the β3 chain transmembrane helix in model systems and this may reflect a stage in the process of inside-out signalling which primes integrins. Moreover, talin proteins are able to dimerize and thus are thought to intervene in the clustering of integrin dimers which leads to the formation of a focal adhesion. Recently, the Kindlin-1 and Kindlin-2 proteins have also been found to interact with integrin and activate it.

Function

Integrins have two main functions:-

• 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, including immune patrolling, cell migration, and binding to cells by certain viruses, such as adenovirus, echovirus, hantavirus, and foot and mouth disease viruses.

A prominent function of the integrins is seen in the molecule GPIIbIIIa, an integrin on the surface of blood platelets (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIbIIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.

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 defined by which α and β subunits the integrin is made of. Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the cell and the ECM may help 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.

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 of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion complexes, which consist of integrins and many cytoplasmic proteins, such as talin, vinculin, paxillin, and alpha-actinin. These act by regulating kinases such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as CRK. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin alpha6beta4 is an exception: it links to the keratin intermediate filament system in epithelial cells.

Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy. As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5 nm and spaced at approximately 45 nm. Treatment with Rho-kinase inhibitor Y-27632 reduces the size of the particle, and it is extremely mechanosensitive.

One important function of integrins on cells in tissue culture is their role in cell migration. Cells adhere to a substrate through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis; they are transported through the cell to its front by the endocytic cycle, where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front. It is not yet clear whether cell migration in tissue culture is an artefact of integrin processing, or whether such integrin-dependent cell migration also occurs in living organisms.

Signal transduction

Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor. In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules.

The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through assembly of adhesomes.

Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience:

• cell growth,
• cell division,
• cell survival,
• cellular differentiation, and
• apoptosis (programmed cell death).

Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach for inhibiting angiogenesis.

Vertebrate integrins

The following are some of the integrins found in vertebrates:

Name	Synonyms	Distribution	Ligands
α1β1	VLA-1	Many	Collagens, laminins
α2β1	VLA-2	Many	Collagens, laminins
α3β1	VLA-3	Many	Laminin-5
α4β1	VLA-4	Hematopoietic cells	Fibronectin, VCAM-1
α5β1	VLA-5; fibronectin receptor	widespread	fibronectin and proteinases
α6β1	VLA-6; laminin receptor	widespread	laminins
α7β1		muscle, glioma	laminins
αLβ2	LFA-1	T-lymphocytes	ICAM-1, ICAM-2
αMβ2	Mac-1, CR3	Neutrophils and monocytes	Serum proteins, ICAM-1
αIIbβ3	Fibrinogen receptor; gpIIbIIIa	Platelets	fibrinogen, fibronectin
αVβ1		ocular melanoma; neurological tumors	vitronectin; fibrinogen
αVβ3	vitronectin receptor	activated endothelial cells, melanoma, glioblastoma	vitronectin, fibronectin, fibrinogen, osteopontin, Cyr61
αVβ5		widespread, esp. fibroblasts, epithelial cells	vitronectin and adenovirus
αVβ6		proliferating epithelia, esp. lung and mammary gland	fibronectin; TGFβ1+3
αVβ8		neural tissue; peripheral nerve	fibronectin; TGFβ1+3
α6β4		Epithelial cells	Laminin

Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which suggests that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors — also by inducing a shape change — to trigger outside-in signal transduction.

References

External links

Media related to Integrins at Wikimedia Commons

• MBInfo - Integrin-Mediated Signalling
• MBInfo - Integrin Activation
• Eukaryotic Linear Motif resource motif class LIG_RGD
• Eukaryotic Linear Motif resource motif class LIG_Integrin_isoDGR_1
• The Integrin Protein
• Talin substrate for calpain – PMAP The Proteolysis Map animation.
• Integrins at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 炎症の病因における白血球内皮細胞接着 leukocyte endothelial adhesion in the pathogenesis of inflammation
• 2. 成人における重症または難治性クローン病の内科的マネージメントの概要 overview of the medical management of severe or refractory crohn disease in adults
• 3. 成人におけるステロイド抵抗性およびステロイド依存性の潰瘍性大腸炎に対するアプローチ approach to adults with steroid refractory and steroid dependent ulcerative colitis
• 4. Leukocyte-adhesion deficiency
• 5. クローン病の内科的マネージメントにおける試験研究治療 investigational therapies in the medical management of crohn disease

English Journal

• A multifunctional streptococcal collagen-mimetic protein coating prevents bacterial adhesion and promotes osteoid formation on titanium.

• Bronk JK1, Russell BH2, Rivera JJ2, Pasqualini R3, Arap W3, Höök M4, Barbu EM5.
• Acta biomaterialia.Acta Biomater.2014 Jul;10(7):3354-62. doi: 10.1016/j.actbio.2014.04.005. Epub 2014 Apr 13.
• The major barriers to the clinical success of orthopedic and dental implants are poor integration of fixtures with bone tissue and biomaterial-associated infections. Although multifunctional device coatings have long been considered a promising strategy, their development is hindered by difficulties
• PMID 24732634

• The PDZ-binding domain of syndecan-2 inhibits LFA-1 high-affinity conformation.

• Rovira-Clavé X1, Angulo-Ibáñez M2, Reina M3, Espel E4.
• Cellular signalling.Cell Signal.2014 Jul;26(7):1489-99. doi: 10.1016/j.cellsig.2014.03.012. Epub 2014 Mar 21.
• Syndecans are cell membrane proteoglycans that can modulate the activity and dynamics of some growth factor receptors and integrins. Here, we show the down-regulation of integrin lymphocyte function-associated antigen-1 (LFA-1) and inhibition of adhesion of Jurkat T cells transfected with syndecan-2
• PMID 24662262

• Effects of astrocyte-targeted production of interleukin-6 in the mouse on the host response to nerve injury.

• Almolda B1, Villacampa N, Manders P, Hidalgo J, Campbell IL, González B, Castellano B.
• Glia.Glia.2014 Jul;62(7):1142-61. doi: 10.1002/glia.22668. Epub 2014 Apr 2.
• Interleukin-6 (IL-6) is a pleiotropic cytokine with a key role in the control of inflammatory/immune responses. In the central nervous system (CNS), an increase in IL-6 occurs in a wide range of pathological conditions such as excitotoxicity and traumatic brain injury. We evaluated the effects of as
• PMID 24691898

Japanese Journal

• Co-Overexpression of GEP100 and AMAP1 Proteins Correlates with Rapid Local Recurrence after Breast Conservative Therapy

• Kinoshita Rumiko,Nam Jin-Min,Ito Yoichi M.,Hatanaka Kanako C.,Hashimoto Ari,Handa Haruka,Otsuka Yutaro,Hashimoto Shigeru,Onodera Yasuhito,Hosoda Mitsuchika,Onodera Shunsuke,Shimizu Shinichi,Tanaka Shinya,Shirato Hiroki,Tanino Mishie,Sabe Hisataka
• Plos one 8(10), e76791, 2013-10-07
• … This pathway activates beta 1 integrins and perturbs E-cadherin-based adhesions, hence appears to be integral for epithelial-mesenchymal transdifferentiation (EMT). …
• NAID 120005348196

• インテグリンを標的とした骨形成および骨修復の促進

• Marie Pierre J.
• Nature reviews. Endocrinology 6(2), 60-67, 2013-10
• NAID 40019845179

• Bimodal anti-glioma mechanisms of cilengitide demonstrated by novel invasive glioma models

• Onishi Manabu,Ichikawa Tomotsugu,Kurozumi Kazuhiko,Fujii Kentaro,Yoshida Koichi,Inoue Satoshi,Michiue Hiroyuki,Chiocca E. Antonio,Kaur Balveen,Date Isao
• Neuropathology 33(2), 162-174, 2013-04
• … Integrins are expressed in tumor cells and tumor endothelial cells, and likely play important roles in glioma angiogenesis and invasion. …
• NAID 120005311964

Related Links

• Integrins - National Center for Biotechnology Information

When integrins were being identified with antibodies to integrin β subunits, several proteins were co-immunoprecipitated, and the number of subunits that composed the functional receptors was by no means obvious.

• Integrins - Molecular Biology of the Cell - NCBI Bookshelf

The binding of integrins to their ligands depends on extracellular divalent cations (Ca 2+ or Mg 2+, depending on the integrin), reflecting the presence of divalent-cation-binding domains in the extracellular part of the α and β subunits.

• Flash Intro Page

Enter Site

Related Pictures

---

★リンクテーブル★

リンク元	「インテグリン」
関連記事	「integrin」

「インテグリン」

　　[★]

英

integrin, integrins

関

インテグリン IMM.87

name			tissue distribution					ligand
			単球	T細胞	マクロファージ	好中球	樹状細胞
αL:β2	LFA-1	CD11a:CD18	○	○	○	○	○	ICAMs
αM:β2	CR3, Mac-1	CD11b:CD18	○		○	○		ICAM-1, iC3b, fibrinogen
αｘ:β2	CR4, p150.90	CD11c:CD18			○	○	○	iC3b
α5:β1	VLA-5	CD49d:CD29	○		○			fibronectin

「integrin」

　　[★] インテグリン

同

integrins