The cytosolic tail of the tumor marker protein Trop2 - a structural switch triggered by phosphorylation

Pavšič, Miha; Ilc, Gregor; Vidmar, Tilen; Plavec, Janez; Lenarčič, Brigita

doi:10.1038/srep10324

Cited by 23 publications

(18 citation statements)

References 65 publications

(84 reference statements)

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“…In this motif, there is a serine at position 303, which may be phosphorylated by protein kinase C (PKC) ( Figure 1 ) [ 10 ]. This phosphorylation leads to conformational changes and affects the accessibility of functionally important regions of its cytoplasmic tail [ 11 ]. It has been shown that Trop2 extracellular domains can form dimers [ 12 ].…”

Section: Gene and Proteinmentioning

confidence: 99%

“…It has been shown that Trop2 extracellular domains can form dimers [ 12 ]. Using molecular dynamic simulations, Pavšič et al later demonstrated that the Trop2 dimerization interface extends to the transmembrane part [ 11 ]. However, the effect of dimerization on Trop2 function has not yet been studied in detail.…”

Section: Gene and Proteinmentioning

confidence: 99%

“…This phosphorylation is critical for the highly motile phenotype of colorectal carcinoma cells [ 13 ]. Interestingly, there are no serine residues equivalent to Trop2 S303 and S322 in EpCAM, suggesting a differences in signaling properties of cytoplasmic domains of both proteins [ 11 ]. Both proteins also differ in the number of glycosylation sites ( Figure 1 ).…”

Section: Gene and Proteinmentioning

confidence: 99%

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Trop2: Jack of All Trades, Master of None

Lenárt

Šmarda

et al. 2020

Cancers

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Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug–antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.

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Section: Gene and Proteinmentioning

confidence: 99%

Section: Gene and Proteinmentioning

confidence: 99%

Section: Gene and Proteinmentioning

confidence: 99%

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Trop2: Jack of All Trades, Master of None

Lenárt

Šmarda

et al. 2020

Cancers

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“…A recent report demonstrated that the EpCAM homologous protein Trop-2, with similar functionality, is phosphorylated in Trop-IC, enabling conformational switching. 15 , 16 In light of this, the study aimed to employ an in silico analysis for prediction of novel EpCAM PTM sites. Further, we checked the biological/functional relevance of the PTM based on the impact of the putative PTM on conformational dynamics and functionality of the human EpICD.…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule

et al. 2020

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The epithelial cell adhesion molecule (EpCAM) is a transmembrane cell adhesion glycoprotein, which primarily contributes to stemness, proliferation, and metastasis properties of tumor cells. Regulated intramembrane proteolysis by ADAM proteases and γ-secretase cleaves EpCAM into an ∼27 kDa soluble extracellular and an ∼4 kDa cytoplasmic domain (EpICD). After the EpICD fragment is released inside the cell, the formation of a nuclear signaling complex with the FHL2 molecule is critical for exerting its regulatory role. Trop-2, a homologous protein of EpCAM, undergoes phosphorylation in its cytoplasmic domain (Trop-IC). The phosphorylation of Trop-2 is reported to be crucial for its function. This led us to ask the fundamental question if EpCAM does undergo similar post-translational modification(PTM) like its homologous protein to carry out its diverse biological function. Here, we identify a putative phosphorylation site at Tyr297 located in the cytoplasmic domain of EpCAM. Molecular dynamic simulation (MDS) of 90 ns was carried out to understand the biological/functional relevance of the putative phosphorylation. It was observed that this phosphorylation stabilizes the α-helical structure of the EpICD. Though Tyr297 does not affect the γ-secretase mediated cleavage of EpCAM, it affects the binding of EpICD to FHL2. Docking analysis revealed that phosphorylation mediated structural stability of EpICD positively impacts its binding affinity with FHL2, which was further validated using 100 ns MDS. Phosphorylated EpICD forms higher numbers of hydrogen bonds, salt bridges, and other non-bonded interactions with FHL2, leading to enhanced interactions. This in silico study reveals a potential PTM in the EpICD, providing the basis for future research in understanding the mechanism behind the diverse biological function of EpCAM.

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“…According to molecular dynamics simulations the dimer is additionally stabilized by dimerization of the transmembrane helices of the two subunits [ 11 ]. However, the dimerization interface most probably does not extend to the cytosolic tail (EpIC) considering the analogy to EpCAM paralogue Trop2—while it has been demonstrated that cytosolic tail of Trop2 has a strong potential to form α-helical structure, dimers were not detected [ 33 ]. For EpIC no stable or induced secondary structure has been observed (our unpublished results).…”

Section: The Biological Unit Of Epcam Is a Cis-dimermentioning

confidence: 99%

Current View on EpCAM Structural Biology

Gaber

Lenarčič

Pavšič

2020

Cells

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EpCAM, a carcinoma cell-surface marker protein and a therapeutic target, has been primarily addressed as a cell adhesion molecule. With regard to recent discoveries of its role in signaling with implications in cell proliferation and differentiation, and findings contradicting a direct role in mediating adhesion contacts, we provide a comprehensive and updated overview on the available structural data on EpCAM and interpret it in the light of recent reports on its function. First, we describe the structure of extracellular part of EpCAM, both as a subunit and part of a cis-dimer which, according to several experimental observations, represents a biologically relevant oligomeric state. Next, we provide a thorough evaluation of reports on EpCAM as a homophilic cell adhesion molecule with a structure-based explanation why direct EpCAM participation in cell–cell contacts is highly unlikely. Finally, we review the signaling aspect of EpCAM with focus on accessibility of signaling-associated cleavage sites.

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The cytosolic tail of the tumor marker protein Trop2 - a structural switch triggered by phosphorylation

Cited by 23 publications

References 65 publications

Trop2: Jack of All Trades, Master of None

Trop2: Jack of All Trades, Master of None

In Silico Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule

Current View on EpCAM Structural Biology

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