2015 Group 2 Project

From CellBiology

Extracellular Matrix 2015 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

Projects are now locked for final Assessment.


Integrins are a group of transmembrane cell adhesion proteins which anchor the extracellular matrix to the cytoskeleton of a cell. [1]. The Integrins also play a part in cell to cell adhesion for example, blood cells. However, integrins are not just adhesion proteins, 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 hemostasis.




Integrins were discovered by Richard O Hynes in 1985 after years of research trying to find this protein due to the idea that there must be a transmembrane connections between the extracellular matrix and the cytoskeleton. The major breakthrough to the discovery of integrins was in 1982 by Greve and Gottlieb. [2] They found that JG22 and CSAT which are two monoclonal antibodies prevented the adhesion of myoblasts to matrix coated surfaces. This in turn means that the JG22 and CSAT antigens will cause the adhesion of myoblasts to the matrix which was supported by the immunofluorescence pictures produced in 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. [3]

Future Research


Guys post the major events here if you have any :)

-1982: discovery of monoclonal antibodies

- 1985: discovered by Richard O Hynes

Interest in Integrins

Number of integrin articles over time.png

Graph 1: This graph depicts the number of articles about integrins found on the pubmed database over different decades.

According to Graph 1, there was no research on integrins between 1965-1975 which makes sense as it was discovered in 1985 by Richard O Hynes. There was minimal amounts of research between 1975 and 1985 on integrins which would be due to the fact it was just discovered. 1995 - 2005 had the most interest in researching integrins shown from the graph, however 2005-2015 is not completely accurate as 2015 has not passed. This means that 2005-2015 may have the most interest in researching integrins.

Number of integrin articles over timeII.png

Graph 2: This graph shows the number of articles about integrins found on the pubmed database over the past decade

According to Graph 2, the greatest interest in researching integrins was in 2012. Although over the decade the number of articles was rather constant excluding 2015 as it is still only early in the year. These numbers only give a rough estimate on the interest in researching integrins as some research projects take years to complete.


- http://www.ncbi.nlm.nih.gov/pubmed/6325925/ Ruoshlahti & RGD

- image of richard o hynes

- the immunofluorescence pictures?

- Photo of the extracellular matrix - cytoskeleton connection?


A. Schematics of the alpha and beta subunits of Integrin. B. The different configurational states of Integrin are shown. i - Nonactive 'resting' state. ii - active state. iii - 'clustered' state with ligands attached

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. Therefore, they serve crucial roles 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.

General structure

Integrins are heterodimers formed by the noncovalent bonding of two transmembrane glycoproteins[4]; 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 consists of approximately 1000 amino acids for the α (alpha) subunit and 700 amino acids for the β (beta) subunit. About half of the α subunits possess an I-domain region at the β-propeller which is an important binding site for ligands. Ligand protein binding is essential because it is the way integrins interact with actin cytoskeleton organization and transduction of intracelluar signals. Like the α subunit, the β also possesses an I-domain which functions essentially the same as the α subunit, but is used in situations where the α subunit does not possess its own I-domain. The I-domain allows ligands to bind due to the interactions with the "metal-ion-dependent adhesive site" area termed MIDAS. The MIDAS allows the binding of divalent metal cations, which is essential for ligand binding and thus, integrin activation. In regards to the image 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.


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 specificity that Integrins need for cellular functions.

Functional structure

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. 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.

3D Structure of Integrin
Integrin biochemical structure


General Function

Integrin proteins are present at high concentrations in both active and inactive forms within the cell and largely serve two main cellular functions [3]. Primary observations revealed a key association between these specific proteins and their "integral" relationship with the extracellular matrix and the actin cytoskeleton. In addition, integrins reinforce overall cellular stability by acting as the chief adhesion receptor for extracellular matrix proteins [5]. However, subsequent research has also revealed significant signal transduction pathways that heavily rely on integrin proteins for facilitating cell signaling pathways both within and between cells[6]. 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 Extracellular Matrix (ECM)[7].

Interaction with the Extracellular Matrix

<mediaplayer width='500' height='300'>https://www.youtube.com/watch?v=8BMFqRmbbes</mediaplayer>[8]

Integrin Trafficking

Integrin proteins are constantly being trafficked in and around the cell via clathrin dependent or clathrin independent carrier proteins that follow either a long-loop pathway or a short-loop pathway of transport(see figure X). 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[9].


Fibronectin is an ECM glycoprotein that functions as an adhesion molecule and actively binds to integrin proteins, particularly α5β1 integrins[10]. 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[11].


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. Research shows that β1 integrins play a key role in the regulation of the endocytosis of ECM collagen[12].


Laminins are a group of ECM proteins largely associated with basement membrane assembly[13]and 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[14]. These integrin-laminin interactions help to initiate and regulate the signal transduction pathways associated with the ECM and the cytoskeleton[15]. 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[16].


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[17], to bind the integrin tail and this binding complex then associates with actin filaments from the cytoskeleton[18]. 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[19].

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, and it can be seen that overexpression of particular integrins cause metastases.

--Z3459592 (talk) 18:46, 28 April 2015 (EST) in* a range of cancers? I think the 2nd sentence might be a bit long maybe break it into 2?

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.

From the results of many studies, it is now suggested that integrins are responsible for initiating metastases, and also allowing and driving tumour cells to become independent of the extracellular matrix. In particular, tumour initiating cells, or TICs, have been studied and it has been discovered that they express particular integrins depending on the type of cancer, and that it leads the cancer to develop drug resistance and the ability to metastasise [20]. Subsequently specific integrins on the surface of cancers cells can identify them as TICs, or 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 and the tumour cell integrin αvβ3 then interacts with fibrinogen and other extracellular matrix components to metastasise into the tissue. β1 integrins are another notable group of integrins that contribute to the metastases of cancers[21]. The complexity in interactions between the integrins of tumour cells and the environment beyond the extracellular matrix allows its to metastasise.

--Z3459592 (talk) 18:46, 28 April 2015 (EST) is 'allowing' needed? "and also driving the tumour cells to become independent of the extracellular matrix"

Not only is there the interaction between the overexpression of particular integrins with the ECM and the environment outside of 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[22]. 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[23], however the mechanism which causes the conversion of CAFs is yet unknown. 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[24]. 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[25]. These changes in integrin expression increases the mobility of the tumour cells, and consequently its ability to metastasise. The increase in integrins also increases the integrin mechanotransduction, which induces the MiRNA MiR-8a to affect the amount of HOXA9, a protein which functions as a developmental patterning protein[26]. Phosphatase and tensin homologue (PTEN) transcription is dependent on the amount of HOXA9 in a cell[27], 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 [28].

Another factor to consider is the relationship between the cell-cell adhesions molecules and also the cell-extracellular matrix molecules, namely the integrins, in the process of tumour cells gaining the ability to metastasise. In this case, 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[29]. 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 changed in the actomyosin[30]. 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 cells connection with the extracellular matrix. In tumour cells, especially when integrins are activated, it can be seen that mutated Src phosphorylates the components of adherens junctions[31], and FAK phosphorylates beta-catenin[32], both of these 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 ...(are there more junctions or less..?)

- make sure to add specific examples to the aforementioned specific integrins and reference

NOTES: reference 25572304/ 22505933/23525005 is a review

find labs that do research - future and current images - draw 1+ picture

--Mark Hill (talk) 10:52, 16 April 2015 (EST) Only a figure title and reference link should appear here.


Term Meaning
transmembrane across a cell membrane
- -
- -
to extend table --> if next is green


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 | width=75% style="background: lightgreen; border-bottom:1.5px solid black"|D

if next is white


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  2. <pubmed>7068780</pubmed>
  3. 3.0 3.1 <pubmed>15533754</pubmed>
  4. http://cshperspectives.cshlp.org/content/3/3/a004994.full
  5. <pubmed>4314628</pubmed>
  6. <pubmed>25663697</pubmed>
  7. <pubmed>24481847</pubmed>
  8. Kosi Gramatikoff [Kosigrim], 3/11/2008, Integrin Binding Collagen, https://www.youtube.com/watch?v=8BMFqRmbbes
  9. <pubmed>25663697</pubmed>
  10. <pubmed>25830530</pubmed>
  11. <pubmed>22899715</pubmed>
  12. <pubmed>20107040</pubmed>
  13. <pubmed>193559668</pubmed>
  14. <pubmed>24951930</pubmed>
  15. <pubmed>193559668</pubmed>
  16. <pubmed>193559668</pubmed>
  17. <pubmed>193559668</pubmed>
  18. <pubmed>25830530</pubmed>
  19. <pubmed>22899715</pubmed>
  20. <pubmed>25572304</pubmed>
  21. <pubmed>22505933</pubmed>
  22. <pubmed>3981899</pubmed>
  23. <pubmed>23171795</pubmed>
  24. <pubmed>23797029 </pubmed>
  25. <pubmed>2788004</pubmed>
  26. <pubmed>3981899</pubmed>
  27. <pubmed>3981899</pubmed>
  28. <pubmed>21490305</pubmed>
  29. <pubmed>23525005</pubmed>
  30. <pubmed>16216928</pubmed>
  31. <pubmed>8425900</pubmed>
  32. ,pubmed>16651417</pubmed>