ITGB6
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Integrin beta-6 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''ITGB6''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. It is the β6 subunit of the integrin αvβ6. Integrins are αβ heterodimeric
glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
s 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
integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
s 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 Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...
and frequently found in high density on the surface of carcinomas (synonymous to
cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
of
epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
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.


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 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...
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 Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD (protein), SMAD family of proteins. It acts as a mediator of the signal ...
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 Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein in humans encoded by the ''EIF4E'' gene. eIF4E plays a central role in translation initiation and is involved in regulating protein synthesis. Its activity influences ...
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 Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...
occurs in response to chronic tissue insult and results in the deposit of excess
collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
by activated
fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s 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 Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
,
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
and
pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...
. 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 Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
, 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 Amelogenesis imperfecta (AI) is a congenital disorder which presents with a rare abnormal formation of the Tooth enamel, enamel or external layer of the crown of teeth, unrelated to any systemic or generalized conditions. Enamel is composed mostly ...
, 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 Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderm ...
(synonymous to
cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
of
epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
origin) has prompted research on radiotracers binding to αvβ6. Such tracers, typically consisting of a radioactive atom (referred to as
radiolabel A radioactive tracer, radiotracer, or radioactive label is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide (a radioactive atom). By virtue of its radioactive decay, it can be used to exp ...
) and a biomolecule that selectively binds to αvβ6, are intended to accumulate in tissues with a high fraction of αvβ6-integrin expressing
cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...
(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 Scintigraphy (from Latin ''scintilla'', "spark"), also known as a gamma scan, is a diagnostic test in nuclear medicine, where radioisotopes attached to drugs that travel to a specific organ or tissue (radiopharmaceuticals) are taken internally a ...
. As of January 2025, there are no approved
radiopharmaceuticals Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which ...
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 Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
labeled with the positron emitter
Gallium-68 Natural gallium (31Ga) consists of a mixture of two stable Isotope, isotopes: gallium-69 and gallium-71. Twenty-nine radioisotopes are known, all synthetic, with atomic masses ranging from 60 to 89; along with three nuclear isomer, nuclear isomer ...
, performed especially well in detecting
pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...
, showing high uptake in tumors and low background in the gastrointestinal tract (GI tract). 68Ga-Trivehexin has been experimentally used for clinical
PET imaging Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, re ...
of pancreatic ductal adenocarcinoma, of tonsillar carcinoma
metastasized Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
to the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
, of bronchial mucoepidermoid carcinoma, of disseminated
parathyroid adenoma A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism; there are very few reports of parathyroid adenomas that were not associated with hyperparathyroidism. A human being usually has four parath ...
in the context of the diagnosis of primary hyperparathyroidism (PHPT), and of
papillary thyroid carcinoma Papillary thyroid cancer (papillary thyroid carcinoma, PTC) is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases.Chapter 20 in: 8th edition. It occurs more frequently in women and presents ...
.


Interactions

Integrin beta 6 has been shown to interact with
FHL2 Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the ''FHL2'' gene. LIM proteins contain a highly conserved double zinc finger motif called the LIM domain. Function FHL-2 is thought to have a ...
.


Notes


References


Further reading

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External links


GeneReviews/NCBI/NIH/UW entry on Epidermolysis Bullosa with Pyloric AtresiaITGB6
Info with links in th
Cell Migration Gateway
{{Integrins Integrins