CMAR_A_210919 353..362

Lan Lei Zhe-Nan Ling Xiang-Liu Chen Lian-Lian Hong Zhi-Qiang Ling 1Department of Molecular Oncology, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, 310022, People’s Republic of China; 2The Second Clinical Medical College of Zhejiang Chinese Medicine University, Hangzhou 310053, People’s Republic of China; 3Department of Clinical Medicine, Medical College, Zhejiang University City College, Hangzhou 310015, People’s Republic of China Abstract: The Golgi apparatus is critical in the compartmentalization of signaling cascades originating from the cytoplasmic membrane and various organelles. Scaffold proteins, such as progestin and adipoQ receptor (PAQR)3, specifically regulate this process, and have recently been identified in the Golgi apparatus. PAQR3 belongs to the PAQR family, and was recently described as a tumor suppressor. Accumulating evidence demonstrates PAQR3 is downregulated in different cancers to suppress its inhibitory effects on malignant potential. PAQR3 functions biologically through the pathological regulation of altered signaling pathways. Significant cell proliferation networks, including Ras proto-oncogene (Ras)/mitogenactivated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), insulin, and vascular endothelial growth factor, are closely controlled by PAQR3 for physiologically relevant effects. Meanwhile, genetic/epigenetic susceptibility and environmental factors, may have functions in the downregulation of PAQR3 in human cancers. This study aimed to assess the subcellular localization of PAQR3 and determine its topological features and functional domains, summarizing its effects on cell signaling compartmentalization. The pathophysiological functions of PAQR3 in cancer pathogenesis, metabolic diseases, and developmental ailments were also highlighted.

[1]  Xue You,et al.  PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9. , 2019, Metabolism: clinical and experimental.

[2]  Z. Wang,et al.  PAQR3 Regulates Endoplasmic Reticulum-to-Golgi Trafficking of COPII Vesicle via Interaction with Sec13/Sec31 Coat Proteins , 2018, iScience.

[3]  J. Li,et al.  Progestin and AdipoQ Receptor 3 Upregulates Fibronectin and Intercellular Adhesion Molecule-1 in Glomerular Mesangial Cells via Activating NF-κB Signaling Pathway Under High Glucose Conditions , 2018, Front. Endocrinol..

[4]  Lin Wang,et al.  Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1 , 2018, Hepatology.

[5]  Mei Yang,et al.  Suppressor PAQR3 associated with the clinical significance and prognosis in esophageal squamous cell carcinoma , 2018, Oncology letters.

[6]  Dong Chen,et al.  PAQR3 inhibits proliferation via suppressing PI3K/AKT signaling pathway in non-small cell lung cancer , 2017, Archives of medical science : AMS.

[7]  Y. Yeom,et al.  Metabolic Signaling to Epigenetic Alterations in Cancer , 2017, Biomolecules & therapeutics.

[8]  A. Bychkov,et al.  Aberrant promoter methylation of the PAQR3 gene is associated with prostate cancer. , 2017, Pathology, research and practice.

[9]  A. Tee,et al.  Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. , 2017, Essays in biochemistry.

[10]  M. Coleman,et al.  Public health surveillance of cancer survival in the United States and worldwide: The contribution of the CONCORD programme , 2017, Cancer.

[11]  Jesse K. Placone,et al.  Understanding the extracellular forces that determine cell fate and maintenance , 2017, Development.

[12]  W. Guo,et al.  A synthetic peptide hijacks the catalytic subunit of class I PI3K to suppress the growth of cancer cells. , 2017, Cancer letters.

[13]  H. Wen,et al.  PAQR3 overexpression suppresses the aggressive phenotype of esophageal squamous cell carcinoma cells via inhibition of ERK signaling. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[14]  Yuan-lin Gao,et al.  PAQR3 inhibits the proliferation, migration and invasion in human glioma cells. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[15]  W. Guo,et al.  Subcellular distribution of RAD23B controls XPC degradation and DNA damage repair in response to chemotherapy drugs. , 2017, Cellular signalling.

[16]  H. Fan,et al.  RKTG overexpression inhibits proliferation and induces apoptosis of human leukemia cells via suppression of the ERK and PI3K/AKT signaling pathways. , 2017, Oncology letters.

[17]  Yan Li,et al.  Overexpression of miR-15b-5p promotes gastric cancer metastasis by regulating PAQR3. , 2017, Oncology reports.

[18]  Fang Zhou,et al.  PAQR3 Inhibits the Proliferation and Tumorigenesis in Esophageal Cancer Cells. , 2017, Oncology research.

[19]  F. Guo,et al.  PAQR3 augments amino acid deprivation-induced autophagy by inhibiting mTORC1 signaling. , 2017, Cellular signalling.

[20]  Ying Zhang,et al.  Effect of Tetramethylpyrazine on Atherosclerosis and SCAP/SREBP-1c Signaling Pathway in ApoE−/− Mice Fed with a High-Fat Diet , 2017, Evidence-based complementary and alternative medicine : eCAM.

[21]  W. Guo,et al.  PAQR3 suppresses the proliferation, migration and tumorigenicity of human prostate cancer cells , 2016, Oncotarget.

[22]  B. P. Jain.  An Overview of Unfolded Protein Response Signaling and Its Role in Cancer. , 2017, Cancer biotherapy & radiopharmaceuticals.

[23]  Feiran Wang,et al.  The role of PAQR3 gene promoter hypermethylation in breast cancer and prognosis. , 2016, Oncology reports.

[24]  W. Guo,et al.  Identification of an adaptor protein that facilitates Nrf2-Keap1 complex formation and modulates antioxidant response. , 2016, Free radical biology & medicine.

[25]  Yuan Chen,et al.  PAQR3 gene expression and its methylation level in colorectal cancer tissues , 2016, Oncology letters.

[26]  Z. Wang,et al.  Two-layer regulation of PAQR3 on ATG14-linked class III PtdIns3K activation upon glucose starvation , 2016, Autophagy.

[27]  Zheng Wang,et al.  PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells. , 2016, Carcinogenesis.

[28]  Yi Pan,et al.  PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L‐associated PI3K activity , 2016, The EMBO journal.

[29]  P. Wedegaertner,et al.  PAQR3 regulates Golgi vesicle fission and transport via the Gβγ-PKD signaling pathway. , 2015, Cellular signalling.

[30]  Z. Wang,et al.  PAQR3 modulates cholesterol homeostasis by anchoring Scap/SREBP complex to the Golgi apparatus , 2015, Nature Communications.

[31]  W. Wu,et al.  PAQR3: a novel tumor suppressor gene. , 2015, American journal of cancer research.

[32]  W. Guo,et al.  DDB2 is involved in ubiquitination and degradation of PAQR3 and regulates tumorigenesis of gastric cancer cells. , 2015, The Biochemical journal.

[33]  W. Guo,et al.  PAQR3 modulates H3K4 trimethylation by spatial modulation of the regulatory subunits of COMPASS-like complexes in mammalian cells. , 2015, The Biochemical journal.

[34]  Z. Ling,et al.  PAQR3 expression is downregulated in human breast cancers and correlated with HER2 expression , 2015, Oncotarget.

[35]  Huijun Li,et al.  PAQR3 plays a suppressive role in laryngeal squamous cell carcinoma , 2015, Tumor Biology.

[36]  Zhiqiang Ma,et al.  The tumor suppressor role of PAQR3 in osteosarcoma , 2015, Tumor Biology.

[37]  Jian-Li Hu,et al.  Identification of PAQR3 as a new candidate tumor suppressor in hepatocellular carcinoma. , 2014, Oncology reports.

[38]  Youcheng Xiu,et al.  MicroRNA-137 Upregulation Increases Bladder Cancer Cell Proliferation and Invasion by Targeting PAQR3 , 2014, PloS one.

[39]  Z. Ling,et al.  A Golgi-specific protein PAQR3 is closely associated with the progression, metastasis and prognosis of human gastric cancers. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  Zhiping Hu,et al.  Characterization of Golgi scaffold proteins and their roles in compartmentalizing cell signaling , 2014, Journal of Molecular Histology.

[41]  G. Morrill,et al.  A computational analysis of non-genomic plasma membrane progestin binding proteins: Signaling through ion channel-linked cell surface receptors , 2013, Steroids.

[42]  D. Brewer,et al.  Nonclassical Progesterone Signalling Molecules in the Nervous System , 2013, Journal of neuroendocrinology.

[43]  M. Pilon,et al.  PAQR-2 may be a regulator of membrane fluidity during cold adaptation , 2013, Worm.

[44]  Fei Xiao,et al.  PAQR3 has modulatory roles in obesity, energy metabolism, and leptin signaling. , 2013, Endocrinology.

[45]  J. Borén,et al.  PAQR-2 Regulates Fatty Acid Desaturation during Cold Adaptation in C. elegans , 2013, PLoS genetics.

[46]  D. Brewer,et al.  Novel progesterone receptors: neural localization and possible functions , 2013, Front. Neurosci..

[47]  Zhenzhen Wang,et al.  PAQR3 Modulates Insulin Signaling by Shunting Phosphoinositide 3-Kinase p110α to the Golgi Apparatus , 2013, Diabetes.

[48]  W. Wu,et al.  Leptin Induces Cyclin D1 Expression and Proliferation of Human Nucleus Pulposus Cells via JAK/STAT, PI3K/Akt and MEK/ERK Pathways , 2012, PloS one.

[49]  D. Drucker,et al.  Activation of Enteroendocrine Membrane Progesterone Receptors Promotes Incretin Secretion and Improves Glucose Tolerance in Mice , 2012, Diabetes.

[50]  Z. Ling,et al.  PAQR3 plays a suppressive role in the tumorigenesis of colorectal cancers. , 2012, Carcinogenesis.

[51]  R. González-Méndez,et al.  Characterization and ligand identification of a membrane progesterone receptor in fungi: existence of a novel PAQR in Sporothrix schenckii , 2012, BMC Microbiology.

[52]  P. Thomas,et al.  Progesterone effects on lymphocytes may be mediated by membrane progesterone receptors. , 2012, Journal of reproductive immunology.

[53]  M. Matsuo,et al.  Dielectric studies on the heterogeneity and interfacial property of composites made of polyacene quinone radical polymers and sulfonated polyurethanes. , 2012, The journal of physical chemistry. A.

[54]  Zhenzhen Wang,et al.  PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus , 2011, Cell Research.

[55]  Anuj Kumar,et al.  Phylogenetic and Preliminary Phenotypic Analysis of Yeast PAQR Receptors: Potential Antifungal Targets , 2011, Journal of Molecular Evolution.

[56]  Z. Ling,et al.  Functional cooperation of RKTG with p53 in tumorigenesis and epithelial-mesenchymal transition. , 2011, Cancer research.

[57]  Stephen L. Abrams,et al.  Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health , 2011, Oncotarget.

[58]  D. Heymann,et al.  Public health surveillance , 2011 .

[59]  C. Lange,et al.  Expression of Membrane Progesterone Receptors (mPR/PAQR) in Ovarian Cancer Cells: Implications for Progesterone-Induced Signaling Events , 2010, Hormones & cancer.

[60]  X. Jiang,et al.  RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma , 2010, Oncogene.

[61]  J. Mort,et al.  Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation , 2010, Laboratory Investigation.

[62]  Y. Hannun,et al.  Sphingolipids Function as Downstream Effectors of a Fungal PAQR , 2009, Molecular Pharmacology.

[63]  Zhenzhen Wang,et al.  Characterization of the topology and functional domains of RKTG. , 2008, The Biochemical journal.

[64]  G. Naselli,et al.  Pancreatic Expression and Mitochondrial Localization of the Progestin-AdipoQ Receptor PAQR10 , 2008, Molecular medicine.

[65]  Zhenzhen Wang,et al.  Suppressive function of RKTG on chemical carcinogen-induced skin carcinogenesis in mouse. , 2008, Carcinogenesis.

[66]  Zhenzhen Wang,et al.  RKTG sequesters B-Raf to the Golgi apparatus and inhibits the proliferation and tumorigenicity of human malignant melanoma cells. , 2008, Carcinogenesis.

[67]  Zhenzhen Wang,et al.  Spatial regulation of Raf kinase signaling by RKTG , 2007, Proceedings of the National Academy of Sciences.

[68]  J. Dong,et al.  Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. , 2007, Endocrinology.

[69]  W. Kolch.  Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[70]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[71]  W. Funk,et al.  PAQR Proteins: A Novel Membrane Receptor Family Defined by an Ancient7-Transmembrane Pass Motif , 2005, Journal of Molecular Evolution.

[72]  Richard Marais,et al.  The RAF proteins take centre stage , 2004, Nature Reviews Molecular Cell Biology.

[73]  J. Manola,et al.  Cancer Management and Research Dovepress , 2022 .