Cadherin-1 or Epithelial cadherin(E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the CDH1 gene. [5] Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. CDH1 has also been designated as CD324 (cluster of differentiation 324). It is a tumor suppressor gene. [6] [7]
The discovery of cadherin cell-cell adhesion proteins is attributed to Masatoshi Takeichi, whose experience with adhering epithelial cells began in 1966. [8] His work originally began by studying lens differentiation in chicken embryos at Nagoya University, where he explored how retinal cells regulate lens fiber differentiation. To do this, Takeichi initially collected media that had previously cultured neural retina cells (CM) and suspended lens epithelial cells in it. He observed that cells suspended in the CM media had delayed attachment compared to cells in his regular medium. His interest in cell adherence was sparked, and he moved on to examine attachment in other conditions such as in the presence of protein, magnesium, and calcium. At this point in 1970s, little was understood about the specific roles these ions played. [9] Therefore, Takeichi’s work in discovering calcium’s role in cell-cell adhesion was highly transformative. [10] [11]
Takeichi went on to discover the existence of multiple cadherins, beginning with E-cadherin. Using rats immunized with F9 cells, he worked with an undergraduate student in the Okada laboratory, Noboru Suzuki, to generate mouse antibodies called ECCD1. This antibody blocked cell-adhesion ability and showed a calcium-dependent interaction with its antigen, E-cadherin. [12] They went on to find that ECCD1 reacted to a variety of epithelial cells when comparing antibody distributions. [13] The delay Takeichi experienced in specifically discovering Ecadherin was most likely due to the model he used to initially investigate cell adherence. The chinese hamster V79 cells apparently did not express E-cadherin, but instead 20 other subtypes that have since been discovered. [14]
Cadherin-1 is a classical member of the cadherin superfamily. The encoded protein is a calcium-dependent cell–cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites. [15]
E-cadherin (epithelial) is the most well-studied member of the cadherin family and is an essential transmembrane protein within adherens junctions. In addition to E-cadherin, adherens junctions are composed of the intracellular components, p120-catenin, beta-catenin, and alpha-catenin. [16] Together, these proteins stabilize epithelial tissues and regulate intercellular exchange. The structure of E-cadherin consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and a highly-phosphorylated intracellular domain. This region is vital to beta-catenin binding and, therefore, to E-cadherin function. [17] Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton.
E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction. [18] In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface. [ citation needed ] Cell–cell interactions mediated by E-cadherin are crucial to blastula formation in many animals. [19]
E-cadherin has been known to mediate adhesion-dependent proliferation inhibition by triggering cell cycle exit via contact inhibition of proliferation (CIP) and recruitment of the Hippo pathway. [20] E-cadherin adhesions inhibit growth signals, which initiates a kinase cascade that excludes the transcription factor YAP from the nucleus. Conversely, decreasing cell density (decreasing cell-cell adhesion) or applying mechanical stretch to place E-cadherins under increased tension promotes cell cycle entry and YAP nuclear localization. [21]
E-cadherin has been found to have a role in epithelial morphogenesis and branching, such as during the formation of epithelial buds. Physiologically, branching is an important feature that allows tissues, such as salivary glands and pancreatic buds, to maximize functional surface areas. [22] It has been discovered that the application of appropriate growth factors and extracellular matrix can induce branching in tissue, but the mechanisms of branching appear to differ between single-layered and stratified epithelium. [23] [24]
Single-layered branching occurs as nearby mechanical influences, such as airway smooth muscle cells, cause epithelial sheets buckle. [25] Stratified epithelial cannot respond to stimulus in the same way due to the absence of internal space (i.e. lumen) that allows tissue sheet flexibility. [26] Instead, it appears stratified epithelial buds are generated by the clefting of one original epithelial cell cluster. Investigations in salivary glands revealed that buds expand as new cells are uniformly distributed across the peripheral surface. Surface-derived cells continue to replicate and produce daughter cells, which then move from the interior back to the surface. This movement is maintained by an E-cadherin gradient, in which surface cells have low levels of E-cadherin and interior cells have high levels of E-cadherin. Such a system allows for increased interactions between interior cells, limiting mobility and ensuring they remain more static, while likewise ensuring the surface cells are comparatively less hindered. This gives a fluidity to their movement within the stratified epithelia, until they begin to accumulate at the edges of the forming bud. [27]
While this gradient is important for cell sorting within the tissue layers, additional experiments show that the physical generation of buds is dependent on cell-matrix interactions[13]. As low-E-cadherin cells accumulate at the surface, they tightly adhere to the basement membrane, allowing the epithelia to cleft and bud as the surface area expands and folds. If the structure of the basement membrane is disrupted, such as by collagenase, the low-E-cadherin cells no longer have a barrier to interact with. Surface-derived daughter cells fail to remain at the periphery to initiate budding under these conditions, yet budding can be reestablished with basement membrane restoration.
The adhesive qualities of E-cadherin indicate it could be a relevant player within germ-layer organization during gastrulation. Gastrulation is a fundamental phase of vertebrate development in which three primary germ layers are defined, ectoderm, mesoderm, and endoderm. [28] Cell adhesion has been linked to progenitor sorting, where ectoderm was found to be the least cohesive and mesoderm was comparable to endoderm cohesion. [29] Initial work depleting calcium from media and, more strikingly, the impairment of E-cadherin both greatly impaired primary germ layer cohesion. As cohesive properties of progenitors were further examined, higher concentrations of CDH-1 were found on mesoderm or endoderm than on ectoderm. While adhesion is a factor in gastrulation, the driving factor in cell sorting was instead found to be in cell-cortex tension[15]. Disrupting the actomyosin-dependent cell cortex with actin depolymerizers and myosin-II inhibitors interrupted impeded tension balances and was sufficient to inhibit cell sorting. This is likely because cell sorting is driven by energy minimization. WIthin tissue energetics, tension plays an important role in ensuring: (1) lower surface tension surrounds the higher surface tension germ layers; (2) aggregate surface tension is appropriately increased; and (3) tension is higher at the cell-to-medium interface than cell-to-cell interface[8]. Cellular adhesion must still be considered for a complete understanding of progenitor sorting, as it directly diminishes the energetic effects of tension. Combined, tension and adhesion increase aggregate surface tension, which allows for unique interactions between differing germ layers and appropriate cell sorting. [30]
Cell migration is vital for constructing and maintaining multicellular organization. Morphogenesis involves numerous events of cell migration, such as the migration of epithelial sheets in gastrulation, the neural crest cell migration, or posterior lateral line primordium migration. [31] It is known that cells that begin to internalize at the dorsal surface of the embryo mobilize to extend the axis and direct posterior prechordal plate and notochord precursors. How cells are able to orient themselves during this process is dependent on the protrusions of “follower cells” to guide the leading cells in the appropriate direction. [32]
E-cadherin has an active role in collective cell dynamics, such as by directing the migration of mesendoderm towards the animal pole. [33] It has been demonstrated that the genetic knockdown of E-cadherin results in random orientations of the cellular protrusions, resulting in cellular migration that is random and no longer unified. [34] Knockdowns in leading and following cell groups both resulted in a loss of orientation, which could be rescued by re-expressing E-cadherin. The information E-cadherin transmitted from cell to cell was directional information inherent to cytoskeletal tension. Restoring only the external adhesion capability of E-cadherin was not enough to rescue protrusion orientation during knockdown experiments. The intracellular domain of E-cadherin is essential due to its mechanotransduction characteristics; it interacts with alpha-catenin and vinculin and altogether allows for the mechanosensation of tension. [35] [36] [37] The exact mechanism on how mechanosensation directs actin-rich protrusions is yet to be elucidated, however initial investigations suggest regulation of PI3K activity is involved. [38]
Adherens junctions (AJs) form homotypic dimers between neighboring cells, where the intracellular protein complex interacts with the actomyosin cytoskeleton. p120-catenin controls E-cadherin membrane localization, while β-catenin and α-catenin provide the link that connect AJs to the cytoskeleton. If AJs experience tensile force when β-catenin is bound, the interaction, known as a catch bond interaction, between α-catenin and F-actin is reinforced. This exposes the a previously inaccessible actin binding site within α-catenin. [39] The binding of vinculin to α-catenin offers the protein complex another linkage with actin in addition to recruiting proteins such as Mena/VASP. [40]
Coordination of the actomyosin network between neighboring cells permits collective cellular activity, such as contractility during morphogenesis. This network is better equipped to maintain tissue integrity if under intercellular stress, but should not be considered a static system. E-cadherin is involved in cellular responses and transcriptional activators that impact migration, growth, and reorganization. [41] [42]
E-cadherin interacts with its environment through numerous pathways. One mechanism that it is involved in is the migration of tissue sheets via cryptic lamellipodia. Rac1 and its effectors act at the front edge of this structure to initiate actin polymerization, allowing the cell to generate force at the cellular margin and forward movement. [43] As leader cells extend their lamellipodia, followers also extend protrusions to collect information on where the tissue sheet it moving. Cell migration is dependent on the generation of a polarized state, with Rac1 at the front and Rho-mediated adhesion at the rear. The release of Merlin from cell contacts partially mediates concomitant migration by acting as a mechanochemical transducer. [44] This tumour suppressor protein relocalizes from cortical cell-cell junctions to the cytoplasm during migration to coordinate Rac1 activation. Other pathways can then modulate Merlin activity, such as circumferential actin belts, which suppresses the nuclear export of Merlin and its interaction with E-cadherin. [45]
CDH1 (gene) has been shown to interact with
Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. [63] [64] E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues. [64] E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry. [65] E-cadherin and N-cadherin temporal-spatial expression are tightly regulated during cranial suture fusion in craniofacial development. [66]
Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma. [67]
E-cadherin is a crucial type of cell–cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT. [67]
The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell–cell adhesions again and return to an epithelial state. [67]
Several proteins such as SNAI1, [73] [74] ZEB2, [75] SNAI2, [76] [77] TWIST1 [78] and ZEB1 [79] have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells. Another group of genes, such as AML1, p300 and HNF3, [80] can upregulate the expression of E-cadherin. [81]
In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”. [81]
Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin. [82]
Morphogenesis is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of developmental biology along with the control of tissue growth and patterning of cellular differentiation.
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.
Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred to as the cadherin adhesome.
Cell junctions or junctional complexes are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.
Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.
The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.
Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.
Fascin is an actin bundling protein.
α-Catenin (alpha-catenin) functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and α-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. α-Catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, β-catenin and α-catenin has not been isolated.
Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 . Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.
p120 catenin, or simply p120, also called catenin delta-1, is a protein that in humans is encoded by the CTNND1 gene.
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.
Cadherin-3, also known as P-Cadherin, is a protein that in humans is encoded by the CDH3 gene.
Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.
Stress fibers are contractile actin bundles found in non-muscle cells. They are composed of actin (microfilaments) and non-muscle myosin II (NMMII), and also contain various crosslinking proteins, such as α-actinin, to form a highly regulated actomyosin structure within non-muscle cells. Stress fibers have been shown to play an important role in cellular contractility, providing force for a number of functions such as cell adhesion, migration and morphogenesis.
αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.
Lobular carcinoma in situ (LCIS) is an incidental microscopic finding with characteristic cellular morphology and multifocal tissue patterns. The condition is a laboratory diagnosis and refers to unusual cells in the lobules of the breast. The lobules and acini of the terminal duct-lobular unit (TDLU), the basic functional unit of the breast, may become distorted and undergo expansion due to the abnormal proliferation of cells comprising the structure. These changes represent a spectrum of atypical epithelial lesions that are broadly referred to as lobular neoplasia (LN).
Masatoshi Takeichi is a Japanese cell biologist known for his identification of the cadherin class of adhesion molecules, which plays important roles in the construction of tissues. He shared the 2005 Japan Prize with Erkki Ruoslahti for "fundamental contribution in elucidating the molecular mechanisms of cell adhesion".
PLEKHA7 is an adherens junction (AJ) protein, involved in the junction's integrity and stability.
Hereditary lobular breast cancer is a rare inherited cancer predisposition associated with pathogenic CDH1 (gene) germline mutations, and without apparent correlation with the hereditary diffuse gastric cancer syndrome. Research studies identified novel CDH1 germline variants in women with diagnosed lobular breast cancer and without any family history of gastric carcinoma. Firstly, in 2018 Giovanni Corso et al. defined this syndrome as a new cancer predisposition and the Authors suggested additional clinical criteria to testing CDH1 in lobular breast cancer patients. In 2020, the International Gastric Cancer Linkage Consortium recognized officially that the hereditary lobular breast cancer is a possible independent syndrome. To date, there are reported about 40 families clustering for lobular breast cancer and associated with CDH1 germline mutations but without association with diffuse gastric cancer. Other recent studies demonstrated a possible correlation between hereditary lobular breast cancer and gastric cancer risk.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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