Connective Tissue Growth Factor Is Secreted through the Golgi and Is Degraded in the Endosome

Chen, Youjun; Segarini, Patricia R.; Raoufi, Fahimeh; Bradham, Douglass M.; Leask, Andrew

doi:10.1006/excr.2001.5364

Cited by 68 publications

(60 citation statements)

References 36 publications

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“…1D). CTGF appeared as a double band in cellular homogenates, representing glycosylated and nonglycosylated CTGF (6). In the cell culture supernatant, a higher molecular weight band showed immunoreactivity, which was not further characterized.…”

Section: Characterization Of Primary Human Tubular Epithelial Cellsmentioning

confidence: 93%

Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

Kroening

Neubauer

Wullich

et al. 2010

American Journal of Physiology-Renal Physiology

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Section: Characterization Of Primary Human Tubular Epithelial Cellsmentioning

confidence: 93%

Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

Kroening

Neubauer

Wullich

et al. 2010

American Journal of Physiology-Renal Physiology

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“…Cells were cultured for 24 h in DMEM, 0.5% fetal bovine serum (FBS), and membrane preparations were isolated (Chen et al, 2001b). Equal amounts of protein were subjected to immunoprecipitation analysis with rabbit anti-CCN2 antibody (Abcam) or mouse IgG (Sigma-Aldrich) by using protein G-Sepharose (Pharmacia, Amersham, United Kingdom) as described previously (Holmes et al, 2001).…”

Section: Immunoprecipitation Assaymentioning

confidence: 99%

“…These fibroblasts attach to, remodel, and contract the newly synthesized ECM, providing the tensile strength required for the support function of the dermis (Clark, 1985). Thus, understanding the mechanism underlying the ability of fibroblasts to adhere to ECM components such as fibronectin is a necessary prerequisite to understanding how the new dermis and other connective tissues are being synthesized.Connective tissue growth factor (CCN2), a member of the CCN family of matricellular proteins (Bork, 1993;Lau and Lam, 1999;Moussad and Brigstock, 2000;Perbal, 2001;, is a cysteine-rich protein that is secreted via a 37-amino acid signal sequence (Chen et al, 2001b). Secondary sequence structure predictions have suggested that CCN2 comprises four modules sharing identity with insulin-like growth factor binding proteins, Von Willebrand factor, thrombospondin domain, and a cysteine knot-containing family of growth regulators (Bork, 1993;Lau and Lam, 1999;Moussad and Brigstock, 2000;Perbal, 2001).…”

mentioning

confidence: 99%

CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin

Chen

Abraham

et al. 2004

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In vivo, CCN2 (connective tissue growth factor) promotes angiogenesis, osteogenesis, tissue repair, and fibrosis, through largely unknown mechanisms. In vitro, CCN2 promotes cell adhesion in a variety of systems via integrins and heparin sulfate proteoglycans (HSPGs). However, the physiological relevance of CCN2-mediated cell adhesion is unknown. Here, we find that HSPGs and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) mitogenactivated protein kinase cascade are required for adult human dermal fibroblasts to adhere to CCN2. Endogenous CCN2 directly binds fibronectin and the fibronectin receptors integrins ␣4 ␤1 and ␣5 and syndecan 4. Using Ccn2؊/؊ mouse embryonic fibroblasts, we show that loss of endogenous CCN2 results in impaired spreading on fibronectin, delayed ␣-smooth muscle actin stress fiber formation, and reduced ERK and focal adhesion kinase phosphorylation. These results suggest that a physiological role of CCN2 is to potentiate the ability of fibroblasts to spread on fibronectin, which may be important in modulating fibroblast adhesion to the provisional matrix during tissue development and wound healing. These results are consistent with the notion that a principal function of CCN2 is to modulate receptor/ligand interactions in vivo. INTRODUCTIONHuman skin, the largest organ in the body, acts as a protective barrier between the internal organs and the external environment (Chuong et al., 2002). The barrier function of skin is provided by both the epidermis, which consists of extracellular lipid-like substances and intracellular insoluble keratin (Fuchs and Byrne, 1994), and the dermis, which consists of fibroblasts that produce extracellular matrix (ECM; Kielty and Shuttleworth, 1997).As a response to environmental insults or trauma, or as a consequence of local inflammatory processes, structural damage to skin can occur. The resultant wound-healing response consists of an integrated series of biochemical, immunological, and structural changes culminating in the de novo synthesis of new epithelia, blood vessels, and connective tissue (Werner and Grose, 2003). During this process, fibroblasts synthesize new ECM components, such as collagen and fibronectin (Badylak, 2002). In addition, fibroblasts proliferate and repopulate the wound. These fibroblasts attach to, remodel, and contract the newly synthesized ECM, providing the tensile strength required for the support function of the dermis (Clark, 1985). Thus, understanding the mechanism underlying the ability of fibroblasts to adhere to ECM components such as fibronectin is a necessary prerequisite to understanding how the new dermis and other connective tissues are being synthesized.Connective tissue growth factor (CCN2), a member of the CCN family of matricellular proteins (Bork, 1993;Lau and Lam, 1999;Moussad and Brigstock, 2000;Perbal, 2001;, is a cysteine-rich protein that is secreted via a 37-amino acid signal sequence (Chen et al., 2001b). Secondary sequence structure predictions have suggested that CC...

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“…CCN proteins comprise four modules: an insulin-like growth factor binding protein (IGFBP) domain (module I), a Von Willebrand factor domain (module II), a thrombospondin-homology domain (module III), and a cysteine knot, heparin-binding domain (module IV) (Bork, 1993;Perbal, 2004). Befitting secreted proteins, each also possesses a signal sequence (Lechner et al, 2000;Chen, Y. et al, 2001) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

All in the CCN family: essential matricellular signaling modulators emerge from the bunker

Leask

Abraham

2006

Journal of Cell Science

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603

660

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The CCN family is a group of six secreted proteins that specifically associate with the extracellular matrix. Structurally, CCN proteins are modular, containing up to four distinct functional domains. CCN family members are induced by growth factors and cytokines such as TGFβ and endothelin 1 and cellular stress such as hypoxia, and are overexpressed in pathological conditions that affect connective tissues, including scarring, fibrosis and cancer. Although CCN family members were discovered over a decade ago, the precise biological role, mechanism of action and physiological function of these proteins has remained elusive until recently, when several key mechanistic insights into the CCN family emerged. The CCNs have been shown to have key roles as matricellular proteins, serving as adaptor molecules connecting the cell surface and extracellular matrix (ECM). Although they appear not to have specific high-affinity receptors, they signal through integrins and proteoglycans. Furthermore, in addition to having inherent adhesive abilities that modulate focal adhesions and control cell attachment and migration, they execute their functions by modulating the activity of a variety of different growth factors, such as TGFβ. CCN proteins not only regulate crucial biological processes including cell differentiation, proliferation, adhesion, migration, apoptosis, ECM production, chondrogenesis and angiogenesis, but also have more sinister roles promoting conditions such as fibrogenesis.

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Connective Tissue Growth Factor Is Secreted through the Golgi and Is Degraded in the Endosome

Cited by 68 publications

References 36 publications

Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin

All in the CCN family: essential matricellular signaling modulators emerge from the bunker

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