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Integrin beta 6
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Integrin beta 6
Integrin beta-6 is a protein that in humans is encoded by the ITGB6 gene. It is the β6 subunit of the integrin αvβ6. Integrins are αβ heterodimeric glycoproteins which span the cell's membrane, integrating the outside and inside of the cell. Integrins bind to specific extracellular proteins in the extracellular matrix or on other cells and subsequently transduce signals intracellularly to affect cell behaviour. One α and one β subunit associate non-covalently to form 24 unique integrins found in mammals. While some β integrin subunits partner with multiple α subunits, β6 associates exclusively with the αv subunit. Thus, the function of ITGB6 is entirely associated with the integrin αvβ6. The dimer αvβ6-integrin is expressed by epithelial cells and frequently found in high density on the surface of carcinomas (synonymous to cancers of epithelial origin). This enables targeting of these cancers with pharmaceuticals and functional imaging agents, such as cancer cell specific positron emission tomography (PET) imaging using the αvβ6-integrin targeted radiotracer 68Ga-Trivehexin.
The β6 subunit and ITGB6 sequence was discovered by Professor Dean Sheppard and colleagues at the University of California, San Francisco in the early 1990s in guinea pig cells. Further investigation by research groups from the University of Madrid and University of Auckland found that ITGB6 was located on chromosome 2q at position 24.2.
In the past decade, significant research has been performed toward identifying the location of regions within the ITGB6 gene which both promote and suppress ITGB6 expression. Of note, binding regions for transcription factors STAT3 and C/EBPα were found, and basic normal cell expression of ITGB6 is thought to be regulated primarily by these proteins. Other transcription factors such as Ets-1 and Smad3 have also been shown to increase ITGB6 expression, while Elk1 binding is able to decrease expression. It is also known that ITGB6 expression is regulated epigenetically via histone acetylation.
It is also known that αvβ6 expression is regulated post-transcriptionally. ITGB6 mRNA is characteristically 'weak', meaning it is less likely to be translated than 'strong' mRNA. eIF4E is a protein which binds to 'weak' mRNA to upregulate translation of the protein. Disruption of eIF4E expression results in a significantly reduced expression of ITGB6.
The first ITGB6-knockout mouse model was developed in 1996. The mice grew normally, with no difference in wound healing ability. However, there was a significant amount of inflammation in the skin and lungs. This was the observation eventually leading to the discovery that αvβ6 activates TGF-β1, as the mice had a similar phenotype to TGF-β1 deficient mice. The mice also developed temporary baldness, possibly due to the role αvβ6 plays in hair follicle regeneration.
While both TGF-β-/- and itgb6-/- mice have many similar characteristics, TGF-β1 deficient mice suffer from poorer health and symptoms not observed in itgb6-/- mice. This is because TGF-β1 can still be activated by other proteins such as Thrombospondin-1. In itgb6/thrombospondin 1 (tsp-1) double-null mice, there is a higher incidence of inflammation more consistent with the TGF-β1 null mice phenotype. Additionally, this study observed that the itgb6-/- mice developed many more benign and malignant tumours compared to both the wild type and tsp-1-/- mice.
Studies with longer term follow up of itgb6-/- mice observed an eventual development of emphysema. Matrix metallopeptidase 12 (MMP12) is an enzyme strongly associated with the development of emphysema, and was expressed 200-fold higher compared to the normal mice in alveolar macrophages. The mice also had abnormally large alveoli which worsened as the mice aged.
Another consistent observation in itgb6-/- mice is periodontitis. αvβ6 is expressed in the junctional epithelium of the gums, and is involved in the adhesion of the gingiva to the teeth. Incomplete adhesion of the gums to the teeth can cause 'pockets' to form which are prone to infection, resulting in chronic periodontal disease. Some mice also develop amelogenesis imperfecta, a disorder causing the teeth to develop abnormally.
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Integrin beta 6
Integrin beta-6 is a protein that in humans is encoded by the ITGB6 gene. It is the β6 subunit of the integrin αvβ6. Integrins are αβ heterodimeric glycoproteins which span the cell's membrane, integrating the outside and inside of the cell. Integrins bind to specific extracellular proteins in the extracellular matrix or on other cells and subsequently transduce signals intracellularly to affect cell behaviour. One α and one β subunit associate non-covalently to form 24 unique integrins found in mammals. While some β integrin subunits partner with multiple α subunits, β6 associates exclusively with the αv subunit. Thus, the function of ITGB6 is entirely associated with the integrin αvβ6. The dimer αvβ6-integrin is expressed by epithelial cells and frequently found in high density on the surface of carcinomas (synonymous to cancers of epithelial origin). This enables targeting of these cancers with pharmaceuticals and functional imaging agents, such as cancer cell specific positron emission tomography (PET) imaging using the αvβ6-integrin targeted radiotracer 68Ga-Trivehexin.
The β6 subunit and ITGB6 sequence was discovered by Professor Dean Sheppard and colleagues at the University of California, San Francisco in the early 1990s in guinea pig cells. Further investigation by research groups from the University of Madrid and University of Auckland found that ITGB6 was located on chromosome 2q at position 24.2.
In the past decade, significant research has been performed toward identifying the location of regions within the ITGB6 gene which both promote and suppress ITGB6 expression. Of note, binding regions for transcription factors STAT3 and C/EBPα were found, and basic normal cell expression of ITGB6 is thought to be regulated primarily by these proteins. Other transcription factors such as Ets-1 and Smad3 have also been shown to increase ITGB6 expression, while Elk1 binding is able to decrease expression. It is also known that ITGB6 expression is regulated epigenetically via histone acetylation.
It is also known that αvβ6 expression is regulated post-transcriptionally. ITGB6 mRNA is characteristically 'weak', meaning it is less likely to be translated than 'strong' mRNA. eIF4E is a protein which binds to 'weak' mRNA to upregulate translation of the protein. Disruption of eIF4E expression results in a significantly reduced expression of ITGB6.
The first ITGB6-knockout mouse model was developed in 1996. The mice grew normally, with no difference in wound healing ability. However, there was a significant amount of inflammation in the skin and lungs. This was the observation eventually leading to the discovery that αvβ6 activates TGF-β1, as the mice had a similar phenotype to TGF-β1 deficient mice. The mice also developed temporary baldness, possibly due to the role αvβ6 plays in hair follicle regeneration.
While both TGF-β-/- and itgb6-/- mice have many similar characteristics, TGF-β1 deficient mice suffer from poorer health and symptoms not observed in itgb6-/- mice. This is because TGF-β1 can still be activated by other proteins such as Thrombospondin-1. In itgb6/thrombospondin 1 (tsp-1) double-null mice, there is a higher incidence of inflammation more consistent with the TGF-β1 null mice phenotype. Additionally, this study observed that the itgb6-/- mice developed many more benign and malignant tumours compared to both the wild type and tsp-1-/- mice.
Studies with longer term follow up of itgb6-/- mice observed an eventual development of emphysema. Matrix metallopeptidase 12 (MMP12) is an enzyme strongly associated with the development of emphysema, and was expressed 200-fold higher compared to the normal mice in alveolar macrophages. The mice also had abnormally large alveoli which worsened as the mice aged.
Another consistent observation in itgb6-/- mice is periodontitis. αvβ6 is expressed in the junctional epithelium of the gums, and is involved in the adhesion of the gingiva to the teeth. Incomplete adhesion of the gums to the teeth can cause 'pockets' to form which are prone to infection, resulting in chronic periodontal disease. Some mice also develop amelogenesis imperfecta, a disorder causing the teeth to develop abnormally.
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