Research Papers:

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 and Liming Chen _

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Oncotarget. 2015; 6:2951-2965. https://doi.org/10.18632/oncotarget.3095

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Shiyi Yu1,*, Xiuxiu Cai1,*, Chenxi Wu1, Lele Wu1,Yuzhi Wang1, Yan Liu1, Zhenghong Yu2, Sheng Qin3, Fei Ma3, Jean Paul Thiery4,5,6 and Liming Chen1

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

* These authors contributed equally to this study


Liming Chen, email:

Keywords: CD44, Oncogenesis, Signaling network

Received: October 19, 2014 Accepted: December 24, 2014 Published: December 30, 2014


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.

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