The CCN proteins: important signaling mediators in stem cell differentiation and tumorigenesis
Guo-Wei Zuo1,2, Christopher D. Kohls2,3, Bai-Cheng He1,2, Liang Chen1,2, Wenli Zhang1,4, Qiong Shi1,2, Bing-Qiang Zhang1,2, Quan Kang1,2, Jinyong Luo1,2, Xiaoji Luo1,2, Eric R. Wagner2, Stephanie H. Kim2, Farbod Restegar2, Rex C. Haydon2, Zhong-Liang Deng1,2, Hue H. Luu2, Tong-Chuan He1,2 and Qing Luo1,2
1Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, and The Affiliated Hospitals, Chongqing Medical University, Chongqing, China, 2Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA, 3Miami University, Oxford, OH, USA and 4Department of Orthopaedic Surgery, Huaxi Hospital Affiliated with Sichuan University School of Medicine, Chengdu, Sichuan, China.
Offprint requests to: Tong-Chuan He, MD, PhD, Molecular Oncology Laboratory, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA. e-mail: tche@surgery.bsd.uchicago.edu. Qing Luo, MD, PhD, The Pediatric Research Institute, The Children’s Hospital, Chongqing Medical University, Chongqing 400014, China. e-mail: qingl0101@yahoo.com
Summary. The CCN proteins contain six members, namely CCN1 to CCN6, which are small secreted cysteine-rich proteins. The CCN proteins are modular proteins, containing up to four functional domains. Many of the CCN members are induced by growth factors, cytokines, or cellular stress. The CCNs show a wide and highly variable expression pattern in adult and in embryonic tissues. The CCN proteins can integrate and modulate the signals of integrins, BMPs, VEGF, Wnts, and Notch. The involvement of integrins in mediating CCN signaling may provide diverse context-dependent responses in distinct cell types. CCN1 and CCN2 play an important role in development, angiogenesis and cell adhesion, whereas CCN3 is critical to skeletal and cardiac development. CCN4, CCN5 and CCN6 usually inhibit cell growth. Mutations of Ccn6 are associated with the progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia tarda. In stem cell differentiation, CCN1, CCN2, and CCN3 play a principal role in osteogenesis, chondrogenesis, and angiogenesis. Elevated expression of CCN1 is associated with more aggressive phenotypes of human cancer, while the roles of CCN2 and CCN3 in tumorigenesis are tumor type-dependent. CCN4, CCN5 and CCN6 function as tumor suppressors. Although CCN proteins may play important roles in fine-tuning other major signaling pathways, the precise function and mechanism of action of these proteins remain undefined. Understanding of the biological functions of the CCN proteins would not only provide insight into their roles in numerous cellular processes but also offer opportunities for developing therapeutics by targeting CCN functions. Histol Histopathol 25, 795-806 (2010)
Key words: CCN family, Chondrogenesis, Osteogenesis, Stem Cell Differentiation, Tumorigenesis
DOI: 10.14670/HH-25.795