Pro-prion binds filamin A, facilitating its interaction with integrin beta1, and contributes to melanomagenesis.
Filamin A (FLNA) is an integrator of cell mechanics and signaling. The spreading and migration observed in FLNA sufficient A7 melanoma cells but not in the parental FLNA deficient M2 cells have been attributed to FLNA. In A7 and M2 cells, the normal prion (PrP) exists as pro-PrP, retaining its glycosylphosphatidyl-inositol (GPI) anchor peptide signal sequence (GPI-PSS). The GPI-PSS of PrP has a FLNA binding motif and binds FLNA. Reducing PrP expression in A7 cells alters the spatial distribution of FLNA and organization of actin and diminishes cell spreading and migration. Integrin β1 also binds FLNA. In A7 cells, FLNA, PrP, and integrin β1 exist as two independent, yet functionally linked, complexes; they are FLNA with PrP or FLNA with integrin β1. Reducing PrP expression in A7 cells decreases the amount of integrin β1 bound to FLNA. A PrP GPI-PSS synthetic peptide that crosses the cell membrane inhibits A7 cell spreading and migration. Thus, in A7 cells FLNA does not act alone; the binding of pro-PrP enhances association between FLNA and integrin β1, which then promotes cell spreading and migration. Pro-PrP is detected in melanoma in situ but not in melanocyte. Invasive melanoma has more pro-PrP. The binding of pro-PrP to FLNA, therefore, contributes to melanomagenesis.
Li
Chaoyang
C
Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Yu
Shuiliang
S
Nakamura
Fumihiko
F
Pentikäinen
Olli T
OT
Singh
Neena
N
Yin
Shaoman
S
Xin
Wei
W
Sy
Man-Sun
MS
D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D002465:Cell Movement; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D064448:Filamins; D015972:Gene Expression Regulation, Neoplastic; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
D003285:Contractile Proteins; D064448:Filamins; D017261:Glycosylphosphatidylinositols; D039641:Integrin beta Chains; D008840:Microfilament Proteins; D011328:Prions