A role for the cleaved cytoplasmic domain of E-cadherin in the nucleus

Emma C Ferber1, Mihoko Kajita, Anthony Wadlow

  • 1University College London, London, WC1E 6BT, UK.

Insights

The p120 catenin protein facilitates the nuclear translocation and DNA binding of the cleaved E-cadherin fragment (E-cad/CTF2). This interaction is crucial for regulating nuclear signaling pathways.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Cancer Research

Background:

  • Cell-cell contacts are crucial for intracellular signaling, but their molecular mechanisms remain unclear.
  • E-cadherin, a key cell adhesion molecule, is cleaved by gamma-secretase, releasing the E-cadherin C-terminal fragment 2 (E-cad/CTF2).

Purpose of the Study:

  • To investigate the cellular fate and function of the E-cad/CTF2 fragment.
  • To elucidate the role of p120 catenin (p120) in the nuclear translocation and DNA binding of E-cad/CTF2.
  • To determine if E-cad/CTF2 influences nuclear signaling pathways.

Main Methods:

  • Coexpression of E-cad/CTF2 and p120.
  • Short interfering RNA (siRNA) to knockdown p120.
  • Analysis of nuclear translocation and DNA binding of E-cad/CTF2.
  • Investigation of the p120-Kaiso signaling pathway.

Main Results:

  • p120 enhances the nuclear translocation of E-cad/CTF2.
  • p120 is essential for the nuclear localization of E-cad/CTF2.
  • p120 promotes and is required for E-cad/CTF2 DNA binding.
  • E-cad/CTF2 regulates the p120-Kaiso signaling pathway in the nucleus.

Conclusions:

  • Cleaved E-cadherin (E-cad/CTF2) has a novel nuclear function.
  • p120 catenin plays a critical role in mediating the nuclear functions of E-cad/CTF2.
  • These findings reveal a new layer of complexity in cell-cell contact-mediated signaling.

Related Concept Videos

Structure of Cadherins01:25

Structure of Cadherins

The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins”   is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This diversity of cadherins...
Cadherins in Tissue Organization01:19

Cadherins in Tissue Organization

The cadherins are a superfamily of cell adhesion molecules comprising over 180 variants, with specific tissues expressing a particular combination of cadherin types. Cadherins generally exhibit homophilic binding; i.e., cadherins on one cell bind to cadherins of the same or closely related type on another cell. Thus, cells of the same type have a specific affinity to bind to each other and sort themselves into clusters to form tissues.
Cell Sorting During Development
Cell sorting plays an...
Catenins01:23

Catenins

Catenins are characterized by multiple binding domains and dynamic structures that allow them to function as linker proteins in cell junction complexes. All catenins, except α-catenin, contain a characteristic protein sequence called the armadillo repeat and are therefore also called armadillo proteins.
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
Adherens Junctions01:24

Adherens Junctions

Strong contact points between adjacent cells anchor them to each other, forming tissues. Such anchoring junctions are of two types –  adherens junctions and desmosomes. Adherens junctions are abundant in tissues such as  epithelium and endothelium, forming a continuous zone of adhesion called the adhesion belt. In other tissues, such as  heart muscle, they appear as clusters, linking the cells to produce coordinated heart muscle contraction.
Adherens Junctions are Dynamic
The endothelial cells...
Nuclear Localization Signals and Import01:46

Nuclear Localization Signals and Import

Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of  2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...