2015 Group 2 Project
Projects are now locked for final Assessment.
- 1 Integrins
- 1.1 History
- 1.2 Structure
- 1.3 Function
- 1.4 The Role of Integrins in Disease
- 1.5 Glossary
- 1.6 References
Integrins are a group of transmembrane cell adhesion proteins which anchor the cell to the extracellular matrix (ECM) by its cytoskeleton. Integrins not only anchor the cell, they are also involved in cell to cell adhesion. However, integrins are not just adhesion proteins, as they can also induce intracellular signalling pathways in the extracellular matrix, which makes them play an important role in development, immune response, leukocyte trafficking and haemostasis.
The integrin family is one of the most highly studied cell adhesion receptor within the cell. The family comprises of different combinations of an alpha and a beta subunit joined together. In total there are 18 alpha and 8 beta subunits which can give rise to 24 different integrin receptors. This difference in structure causes integrins to have different properties and distribution throughout the cell, as well as interactions with different components of the extracellular matrix.  However, for an integrin to function, they must be activated by binding a ligand to its receptor. This page focuses mainly on the structure and function of integrins but also its history and its role in disease.
Integrins were discovered by Richard O Hynes in 1985. He spent many years researching trying to find a protein based on the idea that there must be a transmembrane connections between the extracellular matrix and the cytoskeleton. The major breakthrough was made by Greve and Gottlieb in 1982.  They found that JG22 and CSAT, which are two monoclonal antibodies (an antibody produced by a single clone of cells) prevented the adhesion of myoblasts to synthetically made matrix coated surfaces. This means that these antibodies are binding to their specific antigen within the cell which prevents adhesion. They came to the conclusion that the JG22 and CSAT antigens must be the proteins causing the adhesion of myoblasts to the matrix, which was supported by the immunofluorescence pictures produced in the Clayton Bucks and Rick Horwitz lab. These images showed that these antigens lined up with a variety of cytoskeleton proteins such as fibronectin and actin. From this, Hynes worked with these proteins and was eventually able to prove that they were the transmembrane protein which binded the extracellular matrix to the cytoskeleton of cells.  At the same time, Erkki Ruoslahti also made steps towards the discovery of integrins. He found that the RGD sequence (Arg-Gly-Asp) in fibronectin served as the main receptor which caused cell adhesion. Many of the different types of integrins which have been discovered are now known to recognise this sequence in their adhesion ligand while other types bind to related sequences. 
The discovery of integrins sparked interest in research across various fields such as immunology. There have been thousands of research projects on this protein since its discovery and now it is one of the best understood cell adhesion protein. However, there are still many mysteries to this cell adhesion protein which scientists are trying to unravel.
The main focus for integrin research seems to be heading towards finding its role in cancer. Recently, Lee published an article on insulin-like growth factor binding protein-3 which found that it might be a good cancer therapeutic agent by blocking adhesive activity of integrins in a tumour cell.. This provides a path for future research and the hope that cancer might one day be curable. Other paths in the future research of integrins investigate the role of integrins in the progression and prevention of diseases, such as the prevention of angiogenesis, or growing of new blood vessels, and perhaps even the role of integrins in the progression of viral diseases and infections.
There are still many potential fields, most prominently in the understanding of the role of integrins in many diseases, and therefore it will be paramount to understand these roles, which may provide a stepping stone for therapies to improve and prevent the progression of deadly diseases.
Interest in Integrins
Graph 1: This graph depicts the number of articles about integrins found on the pubmed database by searching 'integrin' since when they were discovered to present year.
According to Graph 1, interest in researching integrins increased drastically in the following years after their discovery. The number of articles published about integrins increased every year until 2005 where it decreased slightly. The highest interest in researching integrins was in 2012 where 3701 articles were published on the pubmed database while the lowest was in 1985. It was expected to be the lowest in 1985 as Richard O Hynes had only just discovered them.
Integrins are cell adhesion molecules that are present on all cells in organic beings. They are essential for cell-cell and cell-matrix interactions (extracellular matrix) as they are involved in mechanotransduction and in actin cytoskeleton organization. Due to the fact that they provide linkage between intracellular and extracellular components, they are implicated in almost all kinds of bodily functions ranging from tissue repair to pathogenesis of disease. Understanding the structure of integrins is thus, essential for the understanding of how integrins interact in the body.
Integrins are heterodimers formed by the noncovalent bonding of two transmembrane glycoproteins; an alpha and beta subunit. As they are transmembrane proteins, they consist of both a relatively large extracellular component and a short cytoplasmic component. The extracellular component of the alpha subunit contains approximately 1000 amino acids, while the extracellular component of the beta subunit contains around 700 amino acids. Some of the alpha subunits contain an I-domain which is vital because it is the binding site for ligands . These ligand proteins activate and determine the way integrins interact with the actin cytoskeleton and initiate the transduction of intracellular signals. The beta subunit also possess an I like domain which functions similarly to the alpha subunit, however, it only plays an important role when the alpha subunit does not contain an I domain. The I domains affinity for a ligand is dependant on the concentration of metal ions such as magnesium. This is because they contain a 'metal ion dependent adhesive site' (MIDAS). This site allows for the binding of metal cations, which is essential for ligand binding and thus, integrin activation. In regards to the Figure 2 on the right, when cations flood to the MIDAS, they form a 'clustering' complex which can be seen in the 3rd state (iii.). This 'clustered' state represents the most active state of integrins, and is what allows integrin to interact with the actin cytoskeleton and/or transduce signals through the plasma membrane 
Figure 4: A simplified image of Integrin subunit structure (Z3415735 Integrin structure simplified.jpg Figure deleted due to copyright violation.)
Integrins are considered trans-membrane proteins. As such, they are produced within the intracellular endoplasmic reticulum and Golgi apparatus components and must embed themselves into the plasma membrane. The protein is assisted through the ER membrane with the help of a trans-location channel. Once the channel closes, the protein is embedded in the ER membrane. Vesicles then break off the ER membrane, containing the trans-membrane protein, and travel to the plasma membrane where they embed into the membrane. This is regulated by normal protein synthesis functions such as STOP sequences and START sequences. The video below helps to visually explain the process of trans-membrane protein synthesis .
Integrins are able to mediate communcations between intracellular and extracellular components due to the fact that they span the plasma membrane. Their complex extracellular components are important for binding to ligands. Ligand binding is essential for Integrins because this allows them to interact with the extracellular matrix for function. Similarily, their intracellular components are important for binding to the cytoskeleton and cytoplasmic elements of the cell. Specifically, they bind to talins and kindlins, which help in mechanotransduction and also assist in preparing integrins for ligand binding in their extracellular component. These details are explained more deeply within Function.
The RGD (Arg-Gly-Asp) sequence is an important structural component in fibronectin proteins as it is the main recognition motif for the integrin family. The RGD sequence is also the receptor of cell adhesion molecules in general. This means that many of the different types of integrins recognise and interact with this specific sequence which results in the cytoskeleton being anchored down to the ECM. The different types of integrins which bind to this sequence can be clearly seen in the table below. 
Table 1: This table demonstrates how the RGD sequence interacts with many different types of integrins compared to other sequences
Mammals possess 18 α subunits and 8 β subunits that can combine to form up to 24 different types of receptors - this range of receptor types is essential for the specificity that integrins need for cellular functions. This range of different configurations can be seen on the table to the right (Table 1).
Integrin proteins are present at high concentrations in both active and inactive forms on the cell membrane and largely serve two main cellular functions . Primarily, observations revealed a key association between these specific proteins and their "integral" relationship with the extracellular matrix (ECM) and the actin cytoskeleton, suggesting a structural role of the proteins within the cell. Further investigations revealed that integrins reinforce overall cellular stability by acting as the chief adhesion receptor for ECM proteins . However, subsequent research has also revealed a secondary function as being responsible for significant signal transduction pathways that heavily rely on integrin proteins for facilitating cell signaling pathways both within and between cells. Overall, integrin functionality is mediated through "inside-out" signalling in which various intracellular binding results in conformational changes to other domains of the integrin that affect their affinity to extracellular ligands and their interactions with the ECM.
Interaction with the Extracellular Matrix
The video below breifly shows how integrins interact with the ECM. It depicts how integrins can be in an active or inactive form depending if an ligand is bound which then allows the integrins to anchor the cytoskeleton to the ECM.
Integrin proteins are constantly being trafficked in and around the cell via clathrin dependent or clathrin independent carrier proteins, and these follow either a long-loop pathway or a short-loop pathway of transport (Figure 5.). These trafficked proteins then undergo a sorting process to determine which proteins are destined for degradation and which are able to be recycled. Integrin recycling provides the cell with a replenished supply of integrins ready to engage in new adhesions with the extracellular matrix. Research suggests that this dynamic recycling mechanism allows for 2-D and 3-D cell migration when paired with proper cell signaling from the extracellular matrix ligands.
Fibronectin is an ECM glycoprotein that functions as an adhesion molecule and actively binds to integrin proteins, particularly α5β1 integrins. Fibronectin-integrin interactions do not exist in a static concentration, but rather exist in a dynamic relationship based on the result of regulated cellular pathways initiated by numerous tensile factors related to the cytoskeleton, focal adhesions and the structural stability of the cell.
The extracellular matrix is maintained and regulated by the remodeling and recycling of a number of proteins including collagen I, the major protein component of the extracellular matrix.In humans, there are four integrins that are known as distinct collagen receptors, α1β1, α2β1, α10β1 and α11β1.Research shows that β1 integrins play a key role in the regulation of the endocytosis of ECM collagen.
Laminins are a group of ECM proteins largely associated with basement membrane assemblyand are known to interact with 10 integrin isoforms, with α3β1, α6β1, α7β1, and α6β4 being most common, in addition to other associated adhesion receptor proteins. These integrin-laminin interactions help to initiate and regulate the signal transduction pathways associated with the ECM and the cytoskeleton. Integrins, along with dystroglycan, facilitate this mediation of signal transduction by acting as signal receptors and relaying activating signals to other associated receptor components of the pathway.
Actin Cytoskeleton Association
An integrin protein exists in either an active or an inactive state, which correspond to associated levels of affinity for various extracellular ligands, such as fibronectin. An integrin will experience a conformational change from an inactivated state to an activated state when talin, a cytoskeletal protein, binds to the tail of a β integrin.Once ligands have engaged with their associated integrins the cytoplasmic domain of the β1 integrin recruits several proteins, including integrin-linked kinases, to bind the integrin tail and this binding complex then associates with actin filaments from the cytoskeleton. Once the activated integrin is bound internally to the cytoskeleton, nearby integrins will then migrate and cluster together to form focal adhesions on the surface of the cell membrane. These focal adhesions act as major anchoring points for the cell.
The Role of Integrins in Disease
There has been no conclusive data in recent and previous research in regards to the role of integrins directly causing disease in individuals, however there has been much interest in the field of cancer. In the last decade, and more so in the last few years, there has been a lot of interest revolving around the role of integrins in the metastatic characteristic of a range of cancers. It can be seen that integrins themselves can be overexpressed, or can interact with other cell adhesion molecules to mark the behavioural change of cancer cells.
Recent Research: Cancer Metastases
Integrins are a significant molecule that allows for the communication between the extracellular matrix and tumour cells. Cells change in response to changes in extracellular matrix, where integrins are the mediators for signalling between the internal and external environment of the cell.
Initiation of Metastasis and Interaction with Extracellular Matrix ComponentsFrom the results of many studies, it is now suggested that integrins are responsible for initiating metastases, and also driving tumour cells to become independent of the extracellular matrix. In particular, as mentioned in the review, tumour initiating cells, or TICs, have been studied and it has been discovered that they express particular integrins, depending on the type of cancer. This ultimately leads the cancer to developing drug resistance and the ability to metastasise . Subsequently, specific integrins on the surface of cancers cells can identify them as TICs, and these features potentially allow doctors to label integrins with their expressed behavioural characteristic in cancer cells. Tumour cells can interact with platelets via platelet integrin αIIbβ3, allowing TICs to travel in the bloodstream and attach onto the endothelium. Following attachment and tumour cell arrest, platelet integrin αIIbβ3 in melanoma cancers, it is mentioned that β1 integrins are another notable group of integrins that contribute to the metastases of cancers. The complexity in interactions between the integrins of tumour cells and the environment beyond the extracellular matrix allows its to metastasise.
Another factor to consider is the relationship between the cell-cell adhesion molecules and also the cell-extracellular matrix molecules, namely the integrins, in the process of tumour cells gaining the ability to metastasise. As mentioned in the review, e-cadherin is a major molecule involved in the association, maintenance and disassociation of adherens junctions by binding to both the actin cytoskeleton via the beta catenin molecules and corresponding e-cadherin molecules on surrounding cells. Both the e-cadherin and the integrin molecules bind to the actin cytoskeleton via mediating molecules, and crosstalk between the two are most likely caused by conformational changes in the actomyosin wrapping the actin filaments. When analysing the proteins involved in both e-cadherin and integrin functionality, it can be see that the proto-oncogene Src and FAK play a role in regulating adherens junctions and also the cell's connection with the extracellular matrix. In tumour cells, especially when integrins are activated, it is observed that mutated Src phosphorylates the components of adherens junctions, and FAK phosphorylates beta-catenin, both of these processes contributing to the breakdown of cell-cell junctions. Mutated Src can also affect the expression of beta catenin on the cell membrane by stopping the endocytosis that allows for beta-catenin to be on the extracellular side of the cell membrane, which affects the actomyosin expression and thus integrin function. This process usually contributes to the metastatic characteristic of tumours.
Stiffening of the Extracellular Matrix
Not only is there the interaction between the overexpression of particular integrins on the cellular membrane and the environment that is the extracellullar matrix, the stiffening of the extracellular matrix around a tumour promotes metastases. It has been shown that some genes have an effect on the extracellular matrix stiffening, in particular MiRNAs which are microRNAs. They play a big role in the regulation of tumour suppressor genes and oncogenes, which induce changes in the extracellular matrix, however what the MiRNAs cause can also depend on mechanic stress. These changes to the extracellular matrix have the potential to increase the expression of some integrins on tumour cells, promoting metastases. It has been suggested that the tumour stroma stiffening is due to some expressions of MiRNA causing fibroblasts to turn into cancer associated fibroblasts (CAFs) which lay down collagen, the key scaffolding protein of the extracellular matrix. However, the mechanism which causes the conversion of CAFs is not yet well understood. The upregulation and downregulation of specific MiRNAs in different cancers are able to influence the plasticity of fibroblasts to allow the scaffolding of the stroma.
It is key to understand the method by which cancers gain the ability to metastasise through the stiffening of the extracellular matrix around them. It is known that the stiffness caused by the laying down of collagen causes integrin mechanotransduction, where the integrins translate the forces from the extracellular matrix to regulate cellular changes. The stiffness promotes the creation of more focal adhesions caused by the activity of focal adhesion kinase (FAK), and the subsequent increased number of integrins causes the change in localisation of different integrins on the tumour cell surface. These changes in integrin expression increases the mobility of the tumour cells, . Phosphatase and tensin homologue (PTEN) transcription is dependent on the amount of HOXA9 in a cell , and subsequent decrease in HOXA9 inhibits PTEN transcription. Therefore, PTEN, as an inhibitor of the phosphoinositide-3 kinase (PI3K) pathway, is unable to fulfil its role of regulating the PI3K pathway. It can be observed that the stiffening of the extracellular matrix allows for the overactivation of the PI3K pathway, which mediates cellular functions that allow for cancer metastases, growth, angiogenesis and many other key processes for the initiation and development of cancers .
Integrins are a diverse transmembrane molecule that serve a role in many different processes that transduce the changes in the extracellular matrix to affect the behaviour of a cell, and this is best illustrated in the roles that integrins have in the metastases of cancer cells. There is more that can be explored in the field, especially regarding the interaction between cancer cell integrins and the integrins of platelets that allow them to survive and metastasise through haematogenous means, and this is the direction that current labs can consider to gain a better understanding of the role of integrins in cancer.
|transmembrane||across a cell membrane|
|CAF||cancer associated fibroblasts with the stroma that develops the tumour's microenvironment in such a way that it encourages growth, angiogenesis and metastases|
|PTEN||tumour suppressor gene that codes for an enzyme that dephosphorylates PI3K, thus inhibiting the PI3K/AKT pathway that promotes cell proliferation, growth and survival|
|MiRNA||microRNA, a small non-coding RNA molecule that is involved in gene silencing and regulation|
|mechanotransduction||the conversion of mechanical stress into electrochemical activity|
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