EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC
Nadim Maghzal1, Hulya A Kayali, Nazanin Rohani
1Department of Biology, McGill University, Montreal, H3A1B1 Quebec, Canada.
Abstract:
Epithelial cell adhesion molecule (EpCAM) is a cell-surface protein highly expressed in embryonic tissues and in malignant carcinomas. We report that EpCAM acts as a potent inhibitor of novel protein kinase C (nPKC) in both embryos and cancer cells. We observed dramatic effects of loss of EpCAM on amphibian embryonic tissues, which include sequentially strong overstimulation of PKC activity and of the Erk pathway, leading to exacerbated myosin contractility, loss of cadherin-mediated adhesion, tissue dissociation, and, ultimately, cell death. We show that PKC inhibition is caused by a short segment of the EpCAM cytoplasmic tail. This motif resembles the pseudosubstrate inhibitory domains of PKCs and binds nPKCs with high affinity. A bioinformatics search reveals the existence of similar motifs in other plasma membrane proteins, most of which are cell-cell adhesion molecules. Thus, direct inhibition of PKC by EpCAM represents a general mode of regulation of signal transduction by cell-surface proteins.
Insights
Epithelial cell adhesion molecule (EpCAM) inhibits novel protein kinase C (nPKC). Loss of EpCAM causes severe embryonic tissue defects due to overstimulated PKC and Erk pathways, impacting cell adhesion and survival.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Epithelial cell adhesion molecule (EpCAM) is a cell-surface protein highly expressed in embryonic and malignant carcinoma tissues.
- Novel protein kinase C (nPKC) plays critical roles in cellular signaling pathways.
Purpose of the Study:
- To investigate the role of EpCAM in regulating nPKC activity.
- To elucidate the mechanism by which EpCAM influences embryonic tissue development and cancer cell behavior.
Main Methods:
- Studied EpCAM function in amphibian embryonic tissues.
- Analyzed the effects of EpCAM loss on PKC and Erk pathway activity.
- Investigated the molecular interaction between EpCAM and nPKC using its cytoplasmic tail segment.
- Performed bioinformatics analysis to identify similar regulatory motifs in other proteins.
Main Results:
- Loss of EpCAM led to significant overstimulation of PKC and Erk pathways in embryonic tissues.
- This overstimulation resulted in increased myosin contractility, loss of cadherin-mediated adhesion, tissue dissociation, and cell death.
- A specific motif in the EpCAM cytoplasmic tail was identified as responsible for nPKC inhibition.
- This inhibitory motif binds nPKCs with high affinity and resembles known pseudosubstrate domains.
Conclusions:
- EpCAM directly inhibits nPKC activity through a pseudosubstrate-like motif in its cytoplasmic tail.
- This direct inhibition is crucial for maintaining normal embryonic development by preventing excessive signaling.
- EpCAM-mediated PKC inhibition represents a general mechanism for cell-surface protein regulation of signal transduction, relevant to both development and cancer.
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