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.