title: Adhesion glycoprotein CD44 functions as an upstream regulator of a network connecting ERK, AKT and Hippo-YAP pathways in cancer progression.
abstract: Targeted therapies are considered to be the future of cancer treatment. However, the mechanism through which intracellular signaling pathways coordinate to modulate oncogenesis remains to be elucidated. In this study, we describe a novel crosstalk among ERK, AKT and Hippo-YAP pathways, with CD44 as an upstream regulator. High cell density leads to activation of ERK and AKT but inactivation of YAP in cancer cells. CD44 modulates cell proliferation and cell cycle but not apoptosis. The expression and activity of cell cycle genes were cooperatively regulated by ERK, AKT and Hippo-YAP signaling pathways through CD44-mediated mechanisms. In addition, CD44 depletion abrogates cancer stem cell properties of tumor initiating cells. Taken together, we described a paradigm where CD44 functions as an upstream regulator sensing the extracellular environment to modulate ERK, AKT and Hippo-YAP pathways which cooperatively control downstream gene expression to modulate cell contact inhibition of proliferation, cell cycle progression and maintenance of tumor initiating cells. Our current study provides valuable information to design targeted therapeutic strategies in cancers.
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Shiyi
authors.initials: S
authors.lastname: Yu
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Cai
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Lele
authors.initials: L
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing, P.R. China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Qin
authors.affiliation: Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ma
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
authors.forename: Liming
authors.initials: L
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D047368:Tumor Burden; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3