Adhesion glycoprotein CD44 functions as an upstream regulator of a network connecting ERK, AKT and Hippo-YAP pathways in cancer progression

Shiyi Yu; Xiuxiu Cai; Chenxi Wu; Lele Wu; Yuzhi Wang; Yan Liu; Zhenghong Yu; Sheng Qin; Fei Ma; Jean Paul Thiery; Liming Chen

doi:10.18632/oncotarget.3095

Adhesion glycoprotein CD44 functions as an upstream regulator of a network connecting ERK, AKT and Hippo-YAP pathways in cancer progression

Oncotarget. 2015 Feb 20;6(5):2951-65. doi: 10.18632/oncotarget.3095.

Authors

Shiyi Yu¹, Xiuxiu Cai¹, Chenxi Wu¹, Lele Wu¹, Yuzhi Wang¹, Yan Liu¹, Zhenghong Yu², Sheng Qin³, Fei Ma³, Jean Paul Thiery^{4

5

6}, Liming Chen¹

Affiliations

¹ The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, P.R. China.
² Department of Medical Oncology, Jinling Hospital, Nanjing, P.R. China.
³ Laboratory for Comparative Genomics and Bioinformatics & Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
⁴ Cancer Science Institute, National University of Singapore, Singapore.
⁵ Institute of Molecular and Cell Biology, A*STAR, Singapore.
⁶ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Animals
Breast Neoplasms / enzymology*
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism*
Female
Hippo Signaling Pathway
Humans
Hyaluronan Receptors / genetics
Hyaluronan Receptors / metabolism*
Mice, Nude
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Neoplastic Stem Cells / enzymology
Neoplastic Stem Cells / pathology
Phosphoproteins / metabolism*
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism*
RNA Interference
Signal Transduction* / drug effects
Time Factors
Transcription Factors
Transfection
Tumor Burden
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
CD44 protein, human
Hyaluronan Receptors
Phosphoproteins
Protein Kinase Inhibitors
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3