The kinase PERK represses translation of the G-protein–coupled receptor LGR5 and receptor tyrosine kinase ERBB3 during ER stress in cancer cells

• Published in: The Journal of biological chemistry 2020-04, Vol.295 (14), p.4591-4603
• Main Authors: Okamoto, Yuka, Saito, Takuya, Tani, Yuri, Toki, Tamami, Hasebe, Akiko, Koido, Masaru, Tomida, Akihiro
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Cell Biology; Cell Line, Tumor; colon cancer; Deoxyglucose - pharmacology; Down-Regulation - drug effects; eIF-2 Kinase - antagonists & inhibitors; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; endoplasmic reticulum stress (ER stress); Endoplasmic Reticulum Stress - drug effects; eukaryotic initiation factor 2 (eIF2); Glycosylation; Half-Life; Heat-Shock Proteins - metabolism; Humans; Indoles - pharmacology; kinase signaling; leucine-rich repeat-containing G-protein–coupled receptor 5(LGR5); Mucoproteins - metabolism; Oncogene Proteins - metabolism; Phosphorylation; protein kinase R-like ER kinase (PERK); protein stability; protein synthesis; Receptor, ErbB-3 - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Unfolded Protein Response; unfolded protein response (UPR)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.010655

As a branch of the unfolded protein response, protein kinase R-like endoplasmic reticulum kinase (PERK) represses global translation in response to endoplasmic reticulum (ER) stress. This pathophysiological condition is associated with the tumor microenvironment in cancer. Previous findings in our lab have suggested that PERK selectively represses translation of some mRNAs, but this possibility awaits additional investigation. In this study, we show that a stem-cell marker protein, leucine-rich repeat-containing G-protein–coupled receptor 5 (LGR5), is rapidly depleted in colon cancer cells during ER stress, an effect that depended on the PERK-mediated translational repression. Indeed, the PERK inhibition led to the accumulation of premature, underglycosylated forms of LGR5, which were produced only at low levels during proper PERK activation. Unlike the mature LGR5 form, which is constitutively degraded regardless of PERK activation, the underglycosylated LGR5 exhibited a prolonged half-life and accumulated inside the cells without being expressed on the cell surface. We also found that Erb-B2 receptor tyrosine kinase 3 (ERBB3) is subjected to a similarly-regulated depletion by PERK, whereas the epidermal growth factor receptor (EGFR), stress-inducible heat-shock protein family A (Hsp70) member 5 (HSPA5), and anterior gradient 2 protein-disulfide isomerase family member (AGR2) were relatively. insensitive to the PERK-mediated repression of translation. These results indicate that LGR5 and ERBB3 are targets for PERK-mediated translational repression during ER stress