Fig. 4: PCSK9 promotes KRAS/MEK/ERK signaling cascade via GGPP. | Nature Communications

Fig. 4: PCSK9 promotes KRAS/MEK/ERK signaling cascade via GGPP.

From: The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

Fig. 4

A Phospho-MAPK antibody array assay of 1CT-AK and SW1116 cells with PCSK9 knockdown or knockout, respectively. p-ERK1/2 and p-CREB were consistently down-regulated. B Active KRAS pulldown assays revealed that PCSK9 depletion suppressed KRAS activation. C Loss of PCSK9 decreased the membrane localization of KRAS. D PCSK9 overexpression in DLD1 cells increased active KRAS expression and its membrane localization. E PCSK9 inhibitors, R-IMPP and PF-0644846, suppressed the activation of KRAS in 1CT-AK and SW1116 cells. F PCSK9 knockdown/knockout in 1CT-AK and SW1116 cells inhibited phosphorylation of MEK, ERK, and p09S6K. G PCSK9 overexpression induced p-MEK and p-ERK in DLD1 cells. H R-IMPP and PF-0644846 inhibited p-ERK and expression of its downstream target Cyclin D3 in APC/KRAS-mutant CRC cell lines. I GGPS1 knockdown abrogated the induction of p-MEK and p-ERK by PCSK9 overexpression in DLD1 cells. J Supplementation of GGPP rescued p-MEK and p-ERK expression in PCSK9 knockout LOVO cells. K Schematic diagram summarizing the molecular mechanism of PCSK9 in APC/KRAS-mutant CRC. Source data are provided as a Source Data file.

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