Catenin

cells. • α-catenin • β-catenin • γ-catenin • δ-catenin All but α-catenin contain armadillo repeats. They exhibit a high degree of protein dynamics, alone or in complex. == Function ==

Several types of catenins work with N-cadherins to play an important role in learning and memory. Cell-cell adhesion complexes are required for simple epithelia in higher organisms to maintain structure, function and polarity. These complexes, which help regulate cell growth in addition to creating and maintaining epithelial layers, are known as adherens junctions and they typically include at least cadherin, β-catenin, and α-catenin. Catenins play roles in cellular organization and polarity long before the development and incorporation of Wnt signaling pathways and cadherins. The primary mechanical role of catenins is to connect cadherins to actin filaments, such as the adhesion junctions of epithelial cells. Most studies investigating catenin actions have focused on α-catenin and β-catenin. β-catenin is particularly interesting as it plays a dual role in the cell. First of all, by binding to cadherin receptor intracellular cytoplasmic tail domains, it can act as an integral component of a protein complex in adherens junctions that helps cells maintain epithelial layers. β-catenin acts by anchoring the actin cytoskeleton to the junctions, and may possibly aid in contact inhibition signaling within the cell. For instance, when an epithelial layer is complete and the adherens junctions indicate that the cell is surrounded, β-catenin may play a role in telling the cell to stop proliferating, as there is no room for more cells in the area. Secondly, β-catenin participates in the Wnt signaling pathway as a downstream target. While the pathway is very detailed and not completely understood, in general, when Wnt is not present, GSK-3B (a member of the pathway) is able to phosphorylate β-catenin as a result of a complex formation that includes β-catenin, AXIN1, AXIN2, APC (a tumor suppressor gene product), CSNK1A1, and GSK3B. Following phosphorylation of the N-terminal Ser and Thr residues of β-catenin, BTRC promotes its ubiquitination, which causes it to be degraded by the TrCP/SKP complex. or they can lead to de-regulated growth in disorders like cancer by responding to mutations in β-catenin, APC or Axin, each of which can lead to this de-regulated β-catenin level stabilization in cells. In F9 cells lacking both β-catenin and plakoglobin, very little E-cadherin and α-catenin accumulated at the cell surface. Mice lacking plakoglobin have cell adhesion defects in many tissues, although β-catenin substitutes for plakoglobin at many cellular junctions. Keratinocytes engineered to not express alpha-catenin have disrupted cell adhesion and activated NF-κB. A tumor cell line with defective δ-catenin, low levels of E-cadherin and poor cell-to-cell adhesion could be restored to normal epithelial morphology and increased E-cadherin levels by expression of normal levels of functional δ-catenin. == Clinical significance ==

As previously mentioned, the same properties of catenin that give it an important role in normal cell fate determination, homeostasis and growth, also make it susceptible to alterations that can lead to abnormal cell behavior and growth. Any changes in cytoskeletal organization and adhesion can lead to altered signaling, migration and a loss of contact inhibition that can promote cancer development and tumor formation. In particular, catenins have been identified to be major players in aberrant epithelial cell layer growth associated with various types of cancer. Mutations in genes encoding these proteins can lead to inactivation of cadherin cell adhesions and elimination of contact inhibition, allowing cells to proliferate and migrate, thus promoting tumorigenesis and cancer development. In normal cells, α-catenin may act as a tumor suppressor and can help prevent the adhesion defects associated with cancer. On the other hand, a lack of α-catenin can promote aberrant transcription, which can lead to cancer. As a result, it can be concluded, that cancers are most often associated with decreased levels of α-catenin. β-catenin also likely plays a significant role in various forms of cancer development. However, in contrast to α-catenin, heightened β-catenin levels may be associated with carcinogenesis. In particular, abnormal interactions between epithelial cells and the extracellular matrix are associated with the over-expression of these β-catenins and their relationship with cadherins in some cancers. Stimulation of the Wnt/β-catenin pathway, and its role in promoting malignant tumor formations and metastases, has also been implicated in cancers. The role of catenin in epithelial-mesenchymal transition (or EMT) has also received a lot of recent attention for its contributions to cancer development. It has been shown that HIF-1α can induce the EMT pathway, as well as the Wnt/β-catenin signaling pathway, thus enhancing the invasive potential of LNCaP cells (human prostate cancer cells). As a result, it is possible that the EMT associated with upregulated HIF-1α is controlled by signals from this Wnt/β-catenin pathway. There are other physiological factors that are associated with cancer development through their interactions with catenins. For instance, higher levels of collagen XXIII have been associated with higher levels of catenins in cells. These heightened levels of collagen helped facilitate adhesions and anchorage-independent cell growth and provided evidence of collagen XXIII's role in mediating metastasis. In another example, Wnt/β-catenin signaling has been identified as activating microRNA-181s in hepatocellular carcinoma that play a role in its tumorigenesis. Recent clinical studies Recently, there have been a number of studies in the lab and in the clinic investigating new possible therapies for cancers associated with catenin. Integrin antagonists and immunochemotherapy with 5-fluorouracil plus polysaccharide-K have shown promising results. In the short-term, combining current treatment techniques with therapeutics targeting catenin-associated elements of cancer might be most effective in treating the disease. By disrupting Wnt/β-catenin signaling pathways, short-term neoadjuvant radiotherapy (STNR) may help prevent clinical recurrence of the disease after surgery, but much more work is needed before an adequate treatment based on this concept can be determined. Lab studies have also implicated potential therapeutic targets for future clinical studies. VEGFR-1 and EMT mediators may be ideal targets for preventing cancer development and metastasis. Additionally, acyl hydrazones have been shown to inhibit the Wnt signaling characteristic of many cancers by destabilizing β-catenin, thus disrupting Wnt signaling and preventing the aberrant cell growth associated with cancer. On the other hand, some treatment concepts involve upregulating the E-cadherin/catenin adhesion system to prevent disruptions in adhesions and contact inhibition from promoting cancer metastasis. One possible way to achieve this, which has been successful in mouse models, is to use inhibitors of Ras activation in order to enhance the functionality of these adhesion systems. Other catenin, cadherin or cell cycle regulators may also be useful in treating a variety of cancers. While recent studies in the lab and in the clinic have provided promising results for treating various catenin-associated cancers, the Wnt/β-catenin pathway may make finding a single correct therapeutic target difficult as the pathway has been shown to elicit a variety of different actions and functions, some of which may possibly even prove to be anti-oncogenic. • Mutations in catenin genes can cause loss of contact inhibition that can promote cancer development and tumor formation. • Mutations associated with aberrant epithelial cell layer growth due to lack of adhesions and contact inhibition • Down-regulated levels of α-catenin • Up-regulated levels of β-catenin • Stimulation of the Wnt/β-catenin pathway • Catenin alteration (and Wnt/β-catenin pathway up-regulation) may help stimulate epithelial-mesenchymal transition (or EMT) • Mutations or aberrant regulation of catenins may also associate with other factors that promote metastasis and tumorigenesis • Treatments focus on correcting aberrant catenin levels or regulating catenin pathways that are associated with cancer development and progression ==References==