Integrin beta 6

Discovery

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.

Mouse models

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.

Function

Integrin αvβ6 is found exclusively on epithelial cells. In most resting normal cells, little ITGB6 is produced, however the highest levels are found in the stomach, gall bladder and lung. ITGB6 levels increase in cells remodelling tissues so αvβ6 expression is increased in development, wound healing, but also in fibrosis and cancer.

The principal function of αvβ6 is the activation of cytokine transforming growth factor-b1 (TGF-β1). Latent-TGF-β1 is bound to the extracellular matrix, covered by its pro-peptide latency associated peptide (LAP). αvβ6 binds LAP, and through cytoskeletal force releases TGF-β1. TGF-β1 regulates multiple processes including cell proliferation, differentiation, angiogenesis, epithelial-mesenchymal-transition (EMT) and immune suppression. These processes combine to heal wounds but when uncontrolled can promote tissue pathologies.

Clinical significance

While αvβ6 promotes normal functions such as wound repair, excess αvβ6 production promotes diseases such fibrosis and cancer. High αvβ6 expression in fibrosis and cancer is usually associated with a poorer prognosis.

Fibrosis

Fibrosis occurs in response to chronic tissue insult and results in the deposit of excess collagen by activated fibroblasts in the matrix resulting in hardening of tissue. Fibroblasts are mesenchymal cells in all tissues that maintain the normal tissue matrix. When they become activated, as occurs in wound healing, they secrete extra matrix proteins and cytokines to promote wound repair. Chronic activation of fibroblasts can result in diseases such as pulmonary fibrosis, where the hardening and thickening of the lung tissue makes it difficult for patients to breathe.

A major driver of fibroblast activation is TGF-β and as αvβ6 expression is increased in response to tissue damage, and is a principal activator of TGF-β, it is therefore a potential drug target in treating fibrosis. αvβ6 can promote fibrosis in kidney, lung and skin, despite αvβ6 being almost absent in their healthy equivalents.

Cancer

Increased αvβ6 expression occurs in up to one third of solid tumours including breast cancer, lung cancer and pancreatic cancer. Because it is not found on most normal cells, it is a potential therapeutic and imaging target in cancer research. When αvβ6 is over-expressed in cancers it often correlates with poorer overall survival.

Integrin αvβ6 promotes tumour progression in multiple ways. Through its cytoplasmic tail it promotes cancer cell migration, increased secretion of matrix metalloproteinases (MMPs) that can degrade the ECM, leading to increased invasion. Intracellular signals generated by αvβ6 increase pErk and pAkt that increase cell proliferation and survival, respectively. Through its extracellular domain it activates TGF-β1 which increases processes that aid cancer progression including angiogenesis, activation of fibroblasts (now called Cancer Associated Fibroblasts), immune suppression. and epithelial-to-mesenchymal transition (EMT) EMT is the process by which epithelial cells adopt a mesenchymal phenotype, breaking away from neighbouring epithelial cells and becoming more migratory, a crucial stage in the development of cancer. In cancer, this promotes invasion of the local healthy tissue and ultimately spread to other parts of the body. αvβ6 can be found in cells which are undergoing EMT.

ITGB6 deficiency

Recorded cases of people who are ITGB6 deficient are rare. The first reported case was in 2013 following whole genome sequencing of a 7-year-old girl with amelogenesis imperfecta, a disease affecting the development of teeth. While multiple patients with amelogenesis imperfecta have since been found to have ITGB6 mutations, there were no other clinical symptoms reported in the majority of these cases.

In 2016 a family in Pakistan were found to have dysfunctional ITGB6 resulting in alopecia, intellectual disabilities and symptoms consistent with amelogenesis imperfecta. The clinical phenotype of these cases does not fully reflect the phenotype observed in mouse models, and of note, there was no reference to any chronic inflammation or emphysema.

Integrin αvβ6 as a drug target

Radiopharmaceuticals

Particularly its overexpression by many types of carcinomas (synonymous to cancers of epithelial origin) has prompted research on radiotracers binding to αvβ6. Such tracers, typically consisting of a radioactive atom (referred to as radiolabel) and a biomolecule that selectively binds to αvβ6, are intended to accumulate in tissues with a high fraction of αvβ6-integrin expressing cells (including but not limited to carcinoma cells). Depending on the type of radiolabel, this approach enables imaging of the distribution of αvβ6-integrin in a patient's body by means of positron emission tomography (PET), single-photon emission computed tomography (SPECT), or scintigraphy.

As of January 2025, there are no approved radiopharmaceuticals targeting αvβ6-integrin. However, several αvβ6-integrin targeted radiotracers are currently being developed for clinical use. First-in-human application of different αvβ6 radiotracers has demonstrated that 68Ga-Trivehexin, a peptide labeled with the positron emitter Gallium-68, performed especially well in detecting pancreatic cancer, showing high uptake in tumors and low background in the gastrointestinal tract (GI tract). 68Ga-Trivehexin has been experimentally used for clinical PET imaging of pancreatic ductal adenocarcinoma, of tonsillar carcinoma metastasized to the brain, of bronchial mucoepidermoid carcinoma, of disseminated parathyroid adenoma in the context of the diagnosis of primary hyperparathyroidism (PHPT), and of papillary thyroid carcinoma.

Interactions

Integrin beta 6 has been shown to interact with FHL2.

Notes

References

References

1. (February 1992). "Chromosomal locations of the genes coding for the integrin beta 6 and beta 7 subunits". Immunogenetics.
2. (March 1994). "Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor". The Journal of Biological Chemistry.
3. "Entrez Gene: ITGB6 integrin, beta 6".
4. (September 2002). "Integrins: bidirectional, allosteric signaling machines". Cell.
5. (July 1990). "Complete amino acid sequence of a novel integrin beta subunit (beta 6) identified in epithelial cells using the polymerase chain reaction". The Journal of Biological Chemistry.
6. (1992). "Chromosomal locations of the genes coding for the integrin beta 6 and beta 7 subunits". Immunogenetics.
7. (2015). "Cloning and characterization of the human integrin β6 gene promoter". PLOS ONE.
8. (June 2007). "Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin beta 6". Molecular and Cellular Biology.
9. (February 2005). "Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma". The Journal of Clinical Investigation.
10. (April 2016). "Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression". The Journal of Biological Chemistry.
11. (May 2018). "Epigenetic regulation of integrin β6 transcription induced by TGF-β1 in human oral squamous cell carcinoma cells". Journal of Cellular Biochemistry.
12. (2003). "Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs". Clinical & Experimental Metastasis.
13. (August 2015). "Integrin β6 can be translationally regulated by eukaryotic initiation factor 4E: Contributing to colonic tumor malignancy". Tumour Biology.
14. (May 1996). "Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin". The Journal of Cell Biology.
15. (February 1999). "The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis". Cell.
16. (April 2005). "Characterization of integrin beta6 and thrombospondin-1 double-null mice". Journal of Cellular and Molecular Medicine.
17. (March 2003). "Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema". Nature.
18. (May 2008). "Absence of alphavbeta6 integrin is linked to initiation and progression of periodontal disease". The American Journal of Pathology.
19. (June 2017). "Suppression of αvβ6 Integrin Expression by Polymicrobial Oral Biofilms in Gingival Epithelial Cells". Scientific Reports.
20. (February 2013). "Critical role for αvβ6 integrin in enamel biomineralization". Journal of Cell Science.
21. (June 1995). "Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling". Journal of Cell Science.
22. (January 1996). "Keratinocytes in human wounds express alpha v beta 6 integrin". The Journal of Investigative Dermatology.
23. (June 2009). "Expression of integrin alphavbeta6 and TGF-beta in scarless vs scar-forming wound healing". The Journal of Histochemistry and Cytochemistry.
24. (July 2009). "Defining the role of integrin alphavbeta6 in cancer". Current Drug Targets.
25. (June 2004). "Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1". The Journal of Cell Biology.
26. (June 2011). "Latent TGF-β structure and activation". Nature.
27. (June 2016). "TGF-β Signaling in Cancer". Journal of Cellular Biochemistry.
28. (October 2012). "TGFβ signalling in context". Nature Reviews. Molecular Cell Biology.
29. (May 2009). "Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis". Journal of Cellular Physiology.
30. (February 2009). "TGF-beta-induced epithelial to mesenchymal transition". Cell Research.
31. (2006). "Transforming growth factor-beta regulation of immune responses". Annual Review of Immunology.
32. (September 2008). "Growth factors and cytokines in wound healing". Wound Repair and Regeneration.
33. (December 2011). "Idiopathic pulmonary fibrosis". Lancet.
34. (December 2009). "TGF-beta induces fibroblast activation protein expression; fibroblast activation protein expression increases the proliferation, adhesion, and migration of HO-8910PM [corrected]". Experimental and Molecular Pathology.
35. (July 2009). "In vivo retargeting of adenovirus type 5 to alphavbeta6 integrin results in reduced hepatotoxicity and improved tumor uptake following systemic delivery". Journal of Virology.
36. (June 2004). "The integrin cytoplasmic-tail motif EKQKVDLSTDC is sufficient to promote tumor cell invasion mediated by matrix metalloproteinase (MMP)-2 or MMP-9". The Journal of Biological Chemistry.
37. (February 2002). "Direct integrin alphavbeta6-ERK binding: implications for tumour growth". Oncogene.
38. (May 2013). "Transforming growth factor-β1 (TGF-β1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts". The Journal of Biological Chemistry.
39. (June 2009). "The basics of epithelial-mesenchymal transition". The Journal of Clinical Investigation.
40. (January 2009). "The role of the integrin alpha v beta6 in regulating the epithelial to mesenchymal transition in oral cancer". Anticancer Research.
41. (April 2005). "The epithelial-mesenchymal transition (EMT) and colorectal cancer progression". Cancer Biology & Therapy.
42. (April 2014). "ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta". Human Molecular Genetics.
43. (April 2014). "A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta". Human Molecular Genetics.
44. (August 2016). "Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability". European Journal of Human Genetics.
45. (October 2021). "It's Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals". Cancers.
46. (October 2023). "Mini review of first-in-human integrin αvβ6 PET tracers". Frontiers in Nuclear Medicine.
47. (March 2022). "PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" αvβ6 with Ga-68-Trivehexin". European Journal of Nuclear Medicine and Molecular Imaging.
48. (November 2024). "αvβ6-integrin targeted PET/CT imaging in pancreatic cancer patients using ⁶⁸Ga-Trivehexin". Frontiers in Nuclear Medicine.
49. (June 2021). "PET/CT imaging of pancreatic carcinoma targeting the "cancer integrin" αvβ6". European Journal of Nuclear Medicine and Molecular Imaging.
50. "Concomitant metastatic head-and-neck cancer and pancreatic cancer assessed by αvβ6-integrin PET/CT using ⁶⁸Ga-Trivehexin: incidental detection of a brain metastasis.". European Journal of Nuclear Medicine and Molecular Imaging. (September 2024)
51. (November 2024). "αvβ6-integrin targeted [⁶⁸Ga]Ga-Trivehexin PET/CT imaging of a rare bronchial mucoepidermoid carcinoma". European Journal of Nuclear Medicine and Molecular Imaging.
52. (July 2024). "⁶⁸Ga-Trivehexin PET/CT: a promising novel tracer for primary hyperparathyroidism". European Journal of Nuclear Medicine and Molecular Imaging.
53. (November 2024). "Cancer-Specific Integrin Imaging With ⁶⁸Ga-Trivehexin: A Potential Imaging for Accurate Staging of Thyroid Malignancy.". Clinical Nuclear Medicine.
54. (October 2000). "The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes". The Journal of Biological Chemistry.