Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization

Abstract

Connective tissue growth factor [CTGF]/CCN2 is a prototypic member of the CCN family of regulatory proteins. CTGF expression is up-regulated in a number of fibrotic diseases, including diabetic nephropathy, where it is believed to act as a downstream mediator of TGF-beta function; however, the exact mechanisms whereby CTGF mediates its effects remain unclear. Here, we describe the role of CTGF in cell migration and actin disassembly in human mesangial cells, a primary target in the development of renal glomerulosclerosis. The addition of CTGF to primary mesangial cells induced cell migration and cytoskeletal rearrangement but had no effect on cell proliferation. Cytoskeletal rearrangement was associated with a loss of focal adhesions, involving tyrosine dephosphorylation of focal adhesion kinase and paxillin, increased activity of the protein tyrosine phosphatase SHP-2, with a concomitant decrease in RhoA and Rac1 activity. Conversely, Cdc42 activity was increased by CTGF. These functional responses were associated with the phosphorylation and translocation of protein kinase C-zeta to the leading edge of migrating cells. Inhibition of CTGF-induced protein kinase C-zeta activity with a myristolated PKC-zeta inhibitor prevented cell migration. Moreover, transient transfection of human mesangial cells with a PKC-zeta kinase inactive mutant (dominant negative) expression vector also led to a decrease in CTGF-induced migration compared with wild-type. Furthermore, CTGF stimulated phosphorylation and activation of GSK-3beta. These data highlight for the first time an integrated mechanism whereby CTGF regulates cell migration through facilitative actin cytoskeleton disassembly, which is mediated by dephosphorylation of focal adhesion kinase and paxillin, loss of RhoA activity, activation of Cdc42, and phosphorylation of PKC-zeta and GSK-3beta. These changes indicate that the initial stages of CTGF mediated mesangial cell migration are similar to those involved in the process of cell polarization. These findings begin to shed mechanistic light on the renal diabetic milieu, where increased CTGF expression in the glomerulus contributes to cellular dysfunction.

Involvement of Cyr61 in growth, migration, and metastasis of prostate cancer cells

“…These results also reflected that loss of Cyr61 in Du145 cells might interfere with the normal regulation of FAs by integrins. It has been reported that CTGF promoted mesangial cell migration by disassembling FAs (Crean et al, 2004). As a high similarity existed in the structure and function between Cyr61 and CTGF, and both of them could serve as ligands for integrins (Brigstock, 2003), it was not strange that Cyr61 regulated FA in a similar way as CTGF does.…”

Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase Cδ-dependent Mechanism

“…It is noteworthy that, contrary to the desensitization of PKC induced by PMA, which is actually a down-regulation, the inhibition of PKC activity by BIM had no significant effect on wild-type astrocyte migration. This suggests that down-regulation of PKC␣ by PMA abrogates its inhibition of PKC, this latter isoform being known to stimulate astrocyte polarization Hall, 2001, 2003) and cell migration (Crean et al, 2004;Petit et al, 2005). Contrary to PMA, BIM should inhibits both PKC␣ and PKC, although less efficiently for this latter, thus possibly explaining the different effects exerted by PMA and BIM on wild-type astrocyte migration.…”

Endothelin 1 Induces β1Pix Translocation and Cdc42 Activation via Protein Kinase A-dependent Pathway

“…Indeed, it has been shown that increased Cdc42 activity results in increased cell motility (34). During initial stages of mesangial cell migration new protrusions are formed at the leading edge of the cell.…”