Elevated LDL-cholesterol (LDLc) levels are a major risk factor for 
cardiovascular disease and atherosclerosis. LDLc is cleared from circulation by 
the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin 9 (PCSK9) 
enhances the degradation of the LDLR in endosomes/lysosomes, resulting in 
increased circulating LDLc. PCSK9 can also mediate the degradation of LDLR 
lacking its cytosolic tail, suggesting the presence of as yet undefined 
lysosomal-targeting factor(s). Herein, we confirm this, and also eliminate a 
role for the transmembrane-domain of the LDLR in mediating its PCSK9-induced 
internalization and degradation. Recent findings from our laboratory also 
suggest a role for PCSK9 in enhancing tumor metastasis. We show herein that 
while the LDLR is insensitive to PCSK9 in murine B16F1 melanoma cells, PCSK9 is 
able to induce degradation of the low density lipoprotein receptor-related 
protein 1 (LRP-1), suggesting distinct targeting mechanisms for these receptors. 
Furthermore, PCSK9 is still capable of acting upon the LDLR in CHO 13-5-1 cells 
lacking LRP-1. Conversely, PCSK9 also acts on LRP-1 in the absence of the LDLR 
in CHO-A7 cells, where re-introduction of the LDLR leads to reduced 
PCSK9-mediated degradation of LRP-1. Thus, while PCSK9 is capable of inducing 
degradation of LRP-1, the latter is not an essential factor for LDLR regulation, 
but the LDLR effectively competes with LRP-1 for PCSK9 activity. Identification 
of PCSK9 targets should allow a better understanding of the consequences of 
PCSK9 inhibition for lowering LDLc and tumor metastasis.