title: The accessory proteins REEP5 and REEP6 refine CXCR1-mediated cellular responses and lung cancer progression.
abstract: Some G-protein-coupled receptors have been reported to require accessory proteins with specificity for proper functional expression. In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. Although REEPs enhanced the expression of a subset of GPCRs, in the absence of REEP5 and REEP6, CXCR1 was expressed in the plasma membrane, but receptor internalization and intracellular clustering of β-arrestin2 following IL-8 treatment were impaired, suggesting that REEP5 and REEP6 might be involved in the ligand-stimulated endocytosis of CXCR1 rather than membrane expression, which resulted in strong cellular responses. In A549 lung cancer cells, which endogenously express CXCR1, the depletion of REEP5 and REEP6 significantly reduced growth and invasion by downregulating IL-8-stimulated ERK phosphorylation, actin polymerization and the expression of genes related to metastasis. Furthermore, an in vivo xenograft model showed that proliferation and metastasis of A549 cells lacking REEP5 and REEP6 were markedly decreased compared to the control group. Thus, REEP5 and REEP6 could be novel regulators of G-protein-coupled receptor signaling whose functional mechanisms differ from other accessory proteins.
authors.affiliation: Graduate School of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Cho Rong
authors.initials: CR
authors.lastname: Park
authors.affiliation: Graduate School of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Dong-Joo
authors.initials: DJ
authors.lastname: You
authors.affiliation: Graduate School of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Sumi
authors.initials: S
authors.lastname: Park
authors.affiliation: Graduate School of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Sunam
authors.initials: S
authors.lastname: Mander
authors.affiliation: Graduate School of International Agricultural Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon, 25354, Republic of Korea.
authors.forename: Da-Eun
authors.initials: DE
authors.lastname: Jang
authors.affiliation: Graduate School of International Agricultural Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon, 25354, Republic of Korea.
authors.forename: Su-Cheong
authors.initials: SC
authors.lastname: Yeom
authors.affiliation: College of Pharmacy, Gachon University, Incheon, 406-840, Republic of Korea.
authors.forename: Seong-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Transplantation Research Institute, Cancer Research Institute, Seoul National University, Yongun-dong, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Department of Physical Medicine and rehabilitation, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Sang Heon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Graduate School of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.affiliation: Graduate School of Medicine, Korea University, Seongbuk-gu, Seoul 02841, Republic of Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D018450:Disease Progression; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011485:Protein Binding; D034622:RNA Interference; D023062:Receptors, Interleukin-8A / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D005136:Eye Proteins; D016209:Interleukin-8; D008565:Membrane Proteins; C426247:REEP5 protein, human; C000619079:REEP6 protein, human; D023062:Receptors, Interleukin-8A