Binding of pro-prion to filamin A: by design or an unfortunate blunder

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.

Figure 1

Drawing of a dimeric FLNA: each monomeric FLNa contains an actin-binding domain (ABD) followed by 24 β-sheet immunoglobulin-linked domains, intersperse between these are two hinge regions, domain 24 is a self-association, dimerization domain.

Figure 2

Diagrammatic drawings of PrP and its processing from pre-pro-PrP to pro-PrP and to a mature, N-glycosylated and GPI-anchored PrP. Residues 1–22 contain the leader peptide sequence. Residues 232–253 contain the GPI-peptide signal sequence.

Figure 3

(a) Normal glycosylated and GPI anchored PrP on the cell surface; (b) pro-PrP on the cell surface using the GPI-PSS as a surrogate transmembrane domain and binds to FLNA just underneath the inner membrane leaflet. The sizes of the PrP and FLNA are not proportional. The size of PrP is approximately corresponding to two FLNA immunoglobulin domains.

Figure 4

A minimum drawing model on the interplay between pro-PrP, FLNA and integrin β1 in A7 cells. Presence of pro-PrP pulls FLNA closer to the inner membrane leaflet, allowing it to interact with integrin β1. When the level of pro-PrP is reduced, FLNA is retracted from the inner membrane leaflet rendering it unable to bind integrin β1. γ and δ are proteins that are normally associated with either FLNA or integrins.