Current View on EpCAM Structural Biology

Gaber, Aljaž; Lenarčič, Brigita; Pavšič, Miha

doi:10.3390/cells9061361

Cited by 17 publications

(17 citation statements)

References 99 publications

(198 reference statements)

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“…Mapping of the TACE cleavage sites onto the EpEX dimerization surface (Tsaktanis et al, 2015) indicated that the cleavage by TACE can take place only when EpCAM is in a monomeric state. Molecular docking of the TACE catalytic domain on EpEX (Gaber, Lenarčič & Pavšič, 2020) also supports this hypothesis by demonstrating that EpCAM dimerization sterically hinders access of TACE to the cleavage site. However, the effect of EpCAM oligomeric state on susceptibility to TACE cleavage has never been experimentally addressed, partly due to the inability to manipulate the EpCAM/EpEX oligomeric state.…”

Section: Introductionmentioning

confidence: 78%

Destabilization of EpCAM dimer is associated with increased susceptibility towards cleavage by TACE

Žagar¹,

Pavšič²,

Gaber³

2021

PeerJ

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The cell-surface protein EpCAM is a carcinoma marker utilized in diagnostics and prognostics, and a promising therapeutic target. It is involved in nuclear signaling via regulated intramembrane proteolysis (RIP). Many aspects of this process are not fully understood, including the events at the molecular level leading to the exposure of cleavage sites, buried at the dimerization interface. To investigate the effect of dimer stability on cleavage susceptibility we prepared two mutants of human EpCAM ectodomain: a monomeric form, and a disulfide-stabilized dimeric form. We show that the disulfide-stabilized dimer is resistant to tumor necrosis factor-α-converting enzyme (TACE) cleavage, while the monomeric form is more susceptible than the predominantly dimeric wild type. This provides experimental evidence that the oligomeric state of EpCAM is a determinant in RIP and demonstrates the usefulness of the oligomeric state-specific mutants in investigations of EpCAM biological function.

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Section: Introductionmentioning

confidence: 78%

Destabilization of EpCAM dimer is associated with increased susceptibility towards cleavage by TACE

Žagar¹,

Pavšič²,

Gaber³

2021

PeerJ

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“…EpCAM and EpCAM2/Trop2 are single transmembrane glycoproteins, with a unique sequence and a unique 3D structure (reviewed in [ 13 ]). They are unrelated to any known CAM.…”

Section: General Features Of Epcammentioning

confidence: 99%

“…This result remains puzzling, since, as we will see below, EpCAM has a clear pro-adhesive activity, at least in the context of early embryos. As for the putative homotypic binding, however, recent extensive biochemical tests have failed to detect any hint of such interaction, and it was thus concluded that EpCAM is unlikely to be a bona fide CAM [ 21 ], reviewed in [ 13 ].…”

Section: General Features Of Epcammentioning

confidence: 99%

EpCAM as Modulator of Tissue Plasticity

Fagotto

2020

Cells

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The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While its name relates to its proposed function as a cell adhesion molecule, EpCAM has been shown to have various signalling functions. In particular, it has been identified as an important positive regulator of cell adhesion and migration, playing an essential role in embryonic morphogenesis as well as intestinal homeostasis. This activity is not due to its putative adhesive function, but rather to its ability to repress myosin contractility by impinging on a PKC signalling cascade. This mechanism confers EpCAM the unique property of favouring tissue plasticity. I review here the currently available data, comment on possible connections with other properties of EpCAM, and discuss the potential significance in the context of cancer invasion.

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“…Both are promising targets in carcinoma diagnosis, prognosis, and therapeutic approaches [ 4 , 5 ], which calls for a detailed functional and structural comparison. While EpCAM has already been structurally characterized [ 6 , 7 , 8 ], no equivalent structural data have been available for Trop2 until now.…”

Section: Introductionmentioning

confidence: 99%

Trop2 Forms a Stable Dimer with Significant Structural Differences within the Membrane-Distal Region as Compared to EpCAM

Pavšič

2021

IJMS

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Trop2 is a cell-surface transmembrane glycoprotein involved in the maintenance of epithelial tissue integrity and is an important carcinoma marker. It shares similar claudin-interaction capacity with its paralogue EpCAM, and both are implicated in signaling triggered by proteolytic cleavage within the ectodomain. However, the cell proliferation-regulating interactions with IGF-1, neuregulin-1, and α5β1 integrin appear to be Trop2-specific. To illuminate the structural differences between Trop2 and EpCAM, we report the first crystal structure of a Trop2 ectodomain dimer and compare it to the analogous part of EpCAM. While the overall fold of the two proteins is similar, the dimers differ. In Trop2, the inter-subunit contacts are more extensive than in EpCAM, and there are two major differences in the membrane-distal regions. The immunogenic N-terminal domain is in Trop2 almost colinear with the dimer interface plain and consequently more laterally exposed, and the cleft of yet unknown functionality between the two subunits is almost absent. Furthermore, the site of initial signaling-associated proteolytic cleavage in Trop2 is accessible in the dimeric state, while in EpCAM dimer destabilization is required. The structural differences highlight the divergent evolutionary path of the two proteins and pave the way for their structure-based utilization in therapy.

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Current View on EpCAM Structural Biology

Cited by 17 publications

References 99 publications

Destabilization of EpCAM dimer is associated with increased susceptibility towards cleavage by TACE

Destabilization of EpCAM dimer is associated with increased susceptibility towards cleavage by TACE

EpCAM as Modulator of Tissue Plasticity

Trop2 Forms a Stable Dimer with Significant Structural Differences within the Membrane-Distal Region as Compared to EpCAM

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