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membrane. In fact, several types of PrP isoforms were implicated in cell adhesion
and migration (Fig. 13.1). Due to its cell surface location, GPI-anchored PrP is
implicated in cell-cell adhesion; in 2002, elevated PrP expression increases cation-
independent cell aggregation, which could be reduced after treatment of the cells
with phosphatidylinositol-specific phospholipase C to release cell surface PrP [ 31 ].
Previously, the PrP fragment which induces cell migration was attributed to amino
acids 106–126, which induces migration of monocyte-derived dendritic cell regu-
lated by neuropeptide substance P [ 32 ]. In addition, PrP peptide (106–126) between
the concentration range 160–640 ng/ml induces murine macrophage cell line Ana-1
chemotaxis in a concentration-dependent manner, and the migration of macrophage
can be inhibited by inhibitors for multiple signaling pathways, implying that PrP-
stimulated macrophage motility is mediated by multiple manners [ 33 ]. A similar
phenomenon was observed when BV-2 microglia cells were treated with PrP frag-
ment (106–126) at the concentration range of 25–100 μM. This peptide stimulates
microglia cell chemotaxis [ 34 ]. However, induction of cell migration by PrP frag-
ment may be simply due to cells that respond to oxidative stress imposed by the
peptide. A better approach to assess whether PrP facilitates cell adhesion or migra-
tion is to knock down/knock out the expression of PrP and detect alteration of cell
behavior. In brain endothelial cells, PrP colocates with platelet endothelial cell
adhesion molecule-1 (PECAM-1) in lipid raft domains. Antibody specific to PrP
has the same efficacy as anti-PECAM-1 antibodies to block the transmigration of
U937 human monocytes as well as freshly isolated monocytic cells when preincu-
bated with U937 or hCMEC/D3 cells [ 35 ], suggesting that PrP is facilitating mono-
cyte transmigration. Dpl plays a similar role in astrocytomas. When Dpl expression
was reduced in IPDDC-A2 cell line, cellular migration was greatly reduced as
assayed by wound healing [ 36 ]. When PrP expression was knocked down in a
mouse brain microvascular endothelial cell line bEND.3, cell migration into the
damaged regions but not cell proliferation was greatly reduced, implicating that PrP
may play a role in neurovascular unit recovery from brain injury such as an isch-
emic insult [ 37 ]. Elevation of epidermal growth factor (EGF) or EGF receptor
(EGFR) signaling often affects cellular processes, including increasing cell motility
Fig. 13.1 Cartoon of several PrP isoforms expressed on cells and the potential interacting partners
for the PrP to initiate cell migration. GPI-anchored unglycosylated PrP binds GAG and VEGFR2
via its KKRPK, activating PI3K-Akt signaling pathway. In this model, PrP is required to localize
in lipid raft (left panel)
13 Prion Protein Exacerbates Tumorigenesis