Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Regulation of cadherin switching The downregulation of E

    2019-09-21


    Regulation of cadherin switching The downregulation of E-cadherin during cadherin switching is induced by multiple mechanisms, including methylation of the E-cadherin promoter and signaling pathways that activate E-cadherin-suppressing transcription factors [[61], [62], [63]]. During the progression of many tumor types, hypermethylation of the E-cadherin promoter is often associated with a more advanced grade of disease [[64], [65], [66]]. One study has shown that methylation of the E-cadherin promoter occurs at early stages of tumorigenesis and it persists throughout tumor progression and is dynamically regulated [67]. In addition, many growth factors and chemokines, such as TGFβ, fibroblast growth factor (FGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and Wnt are known to induce the expression and activity of the EMT transcription factors, including multiple zinc finger family and bHLH family transcription factors, such as Snail, Slug, Twist, ZEB1/2, and E12/E47 through specific signaling pathways. These transcription factors inhibit E-cadherin transcription by binding to E-boxes within the E-cadherin promoter, leading to the downregulation of E-cadherin expression [63,68]. Compared to E-cadherin, the mechanisms that upregulate N-cadherin expression during cadherin switching are still largely unknown. One potential mechanism might be the indirect effect of the downregulation of E-cadherin, since a decrease of E-cadherin can release p120 catenin to bind to N-cadherin and reduce its turnover at the cell surface. Moreover, there are studies showing that the level of N-cadherin is directly regulated by transcription factors. For example, Twist has been shown to bind to an E-box of the N-cadherin gene and upregulate its expression [69]. Additionally, TGFβ has been shown to induce SMAD4-mediated transcription of N-cadherin [49].
    Cell-ECM adhesion and DDRs Cell adhesion to the ECM is essential for tissue integrity and cell polarization [13]. Collagens are major components of the ECM in normal tissues and in tumors, where collagens are produced mainly by fibroblasts and mesenchymal cancer MK 0893 pathway [6]. ECM has important functions in cancer progression. The collagen network deposited in tumors is dynamically regulated and directly interacts with cancer cells and stromal cells to affect cell phenotype and behavior [70]. DDR1 and DDR2 are cell surface receptor tyrosine kinases (RTKs) that bind to fibrillar collagens [8]. Collagen-induced activation of DDRs has been implicated in EMT in cancer and also in cadherin switching [11,12]. These observations suggest that cell-cell adhesion and cell-ECM adhesion are not independent but are closely associated and influenced by the local microenvironment. Both integrins and DDRs are able to induce cadherin switching; however, the two types of collagen receptors are different. Integrin receptors consist of two subunits—α and β [71,72]. In mammals, there are 18 α subunits and 8 β subunits, generating a total of 24 combinations. Each of the subunits has a long N-terminal extracellular domain, a transmembrane segment, and a short C-terminal cytoplasmic domain. Unlike other receptor kinases, integrins do not have detectable enzymatic activity. ECM proteins, such as collagens, bind to the extracellular domain of integrins, causing integrin clustering. The structural changes of integrins will activate other protein tyrosine kinases that mediate the signaling cascade. Integrin receptors are classified according to ligand specificity. ECM proteins typically bind to receptors with conserved motifs. For example, collagen-binding integrin receptors bind to the GFOGER (Gly-Phe-Hyp-Gly-Glu-Arg) region of collagens. All the collagen-binding integrins require a β1 subunit, and it forms heterodimers with different α subunits. Integrins α1β1, α2β1, α10β1, and α11β1 are recognized as collagen receptors. Integrin-ECM interactions lead to the formation of focal adhesions, as well as cell spreading and migration. Focal adhesions are required to activate downstream signaling and lead to actin cytoskeleton reorganization and the activation of various protein tyrosine kinases [73]. Focal adhesion kinase (FAK) was one of the first signaling molecules discovered to be associated with integrin activation [74]. However, how FAK is recruited to focal adhesions is still poorly understood. The conformational change of integrins results in the association of the cytoplasmic tail of the integrin β subunit with the cytoskeletal proteins talin and paxillin. These proteins interact directly with the C-terminal domain of FAK and result in FAK activation. A direct downstream target of FAK is Src, which is a major protein kinase that promotes survival, proliferation, and migration [75]. Other signaling molecules that can be activated by FAK include the Rho GTPases [76].