Structural basis and therapeutic implication of the interaction of CCN proteins with glycoconjugates.
The CCN family of growth factors is composed of six structurally related proteins including the cysteine-rich 61 (Cyr61), connective tissue growth factor (CTGF), nephroblastoma overexpressed (NOV), Wnt-1 induced secreted protein-1 (WISP-1), WISP-2 and WISP-3. Each family member consists of four conserved cysteine rich modular domains with sequence similarity to the insulin like growth factor binding proteins, von Willebrand factor, thrombospondin repeat and the growth factors cysteine knot. The CCN proteins demonstrate a wide variety of biological activities regulating cell adhesion, proliferation, survival, migration, invasion in vitro and tumorigenesis and angiogenesis in vivo. Both cancer promoting and inhibiting roles were proposed for several CCN proteins suggesting that contextual factors could regulate their activities. Consistent with this hypothesis, structural and experimental evidence indicate that the function of these proteins is modulated by their interaction with sulfated glycosaminoglycans. Because the CCN proteins are implicated in the tumorigenic process, they are potential targets for the development of cancer therapeutics. Modulation of their glycosaminoglycan interaction by exogenous, highly sulfated polysaccharides, oligosaccharides or glycosaminoglycan mimetics could prevent their participation in cancer progression. Understanding the structural requirements for their polysaccharide interaction should provide important information to generate glycosaminoglycan-based cancer therapeutics targeting the CCN family of proteins.
Desnoyers
Luc
L
Department of Molecular Oncology, Genentech Inc., m/s 42, 1 DNA Way, South San Francisco, California 94080, USA. desnoyer@gene.com
D000818:Animals; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D016503:Drug Delivery Systems / Q000379:methods; D006001:Glycoconjugates / Q000737:chemistry / Q000502:physiology*; D006025:Glycosaminoglycans / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D015394:Molecular Structure; D055514:Nephroblastoma Overexpressed Protein
C501848:CCN1 protein, human; C526317:CCN2 protein, human; C526319:CCN3 protein, human; D055515:Cysteine-Rich Protein 61; D006001:Glycoconjugates; D006025:Glycosaminoglycans; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D055513:Connective Tissue Growth Factor