Binding of pro-prion to filamin A: by design or an unfortunate blunder
1Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-7288, USA.
Abstract:
Over the last decades, cancer research has focused on tumor suppressor genes and oncogenes. Genes in other cellular pathways has received less attention. Between 0.5% to 1% of the mammalian genome encodes for proteins that are tethered on the cell membrane via a glycosylphosphatidylinositol (GPI)-anchor. The GPI modification pathway is complex and not completely understood. Prion (PrP), a GPI-anchored protein, is infamous for being the only normal protein that when misfolded can cause and transmit a deadly disease. Though widely expressed and highly conserved, little is known about the functions of PrP. Pancreatic cancer and melanoma cell lines express PrP. However, in these cell lines the PrP exists as a pro-PrP as defined by retaining its GPI anchor peptide signal sequence (GPI-PSS). Unexpectedly, the GPI-PSS of PrP has a filamin A (FLNA) binding motif and binds FLNA. FLNA is a cytolinker protein, and an integrator of cell mechanics and signaling. Binding of pro-PrP to FLNA disrupts the normal FLNA functions. Although normal pancreatic ductal cells lack PrP, about 40% of patients with pancreatic ductal cell adenocarcinoma express PrP in their cancers. These patients have significantly shorter survival time compared with patients whose cancers lack PrP. Pro-PrP is also detected in melanoma in situ but is undetectable in normal melanocyte, and invasive melanoma expresses more pro-PrP. In this review, we will discuss the underlying mechanisms by which binding of pro-PrP to FLNA disrupts normal cellular physiology and contributes to tumorigenesis, and the potential mechanisms that cause the accumulation of pro-PrP in cancer cells.
Insights
The prion protein (PrP) binds filamin A (FLNA) in cancer cells, disrupting normal cell functions and contributing to tumor growth. This interaction is linked to poorer survival in pancreatic cancer patients.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Biochemistry
Background:
- Cancer research has historically prioritized oncogenes and tumor suppressor genes, neglecting other cellular pathways.
- Glycosylphosphatidylinositol (GPI)-anchored proteins, representing 0.5-1% of the mammalian genome, are involved in complex pathways that remain incompletely understood.
- The prion protein (PrP), a GPI-anchored protein, is known for its role in neurodegenerative diseases but its normal functions are largely unknown.
Purpose of the Study:
- To investigate the role of the prion protein (PrP) and its interaction with filamin A (FLNA) in cancer development.
- To explore the mechanisms by which pro-PrP binding to FLNA contributes to tumorigenesis.
- To understand the reasons for pro-PrP accumulation in cancer cells.
Main Methods:
- Analysis of PrP expression in pancreatic cancer and melanoma cell lines.
- Investigation of the interaction between pro-PrP and FLNA using binding motif analysis.
- Correlation of pro-PrP expression with patient survival in pancreatic ductal cell adenocarcinoma.
- Comparison of pro-PrP levels in normal versus cancerous tissues (pancreatic ductal cells and melanocytes).
Main Results:
- Pancreatic cancer and melanoma cell lines express pro-PrP, characterized by the retention of its GPI anchor peptide signal sequence (GPI-PSS).
- The GPI-PSS of pro-PrP contains a binding motif for FLNA, a cytolinker protein, and this binding disrupts normal FLNA functions.
- Pro-PrP is absent in normal pancreatic ductal cells but present in about 40% of pancreatic ductal cell adenocarcinomas, correlating with shorter patient survival.
- Pro-PrP is detected in melanoma in situ but not in normal melanocytes, with increased expression in invasive melanoma.
Conclusions:
- The binding of pro-PrP to FLNA disrupts cellular physiology and promotes tumorigenesis.
- Accumulation of pro-PrP in cancer cells is a significant factor in disease progression and patient outcomes.
- Targeting the pro-PrP/FLNA interaction may offer novel therapeutic strategies for pancreatic cancer and melanoma.
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