| First Author | Guo DF | Year | 2019 |
| Journal | Am J Physiol Cell Physiol | Volume | 317 |
| Issue | 3 | Pages | C457-C465 |
| PubMed ID | 31216194 | Mgi Jnum | J:280514 |
| Mgi Id | MGI:6357089 | Doi | 10.1152/ajpcell.00498.2018 |
| Citation | Guo DF, et al. (2019) The Bardet-Biedl syndrome protein complex regulates cell migration and tissue repair through a Cullin-3/RhoA pathway. Am J Physiol Cell Physiol 317(3):C457-C465 |
| abstractText | Cell motility and migration play critical roles in various physiological processes and disease states. Here, we show that the BBBsome, a macromolecule composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1, is a critical determinant of cell migration and wound healing. Fibroblast cells derived from mice or humans harboring a homozygous missense mutation (BBS1(M390R/M390R)) that disrupt the BBSome exhibit defects in migration and wound healing. Furthermore, we demonstrate that BBS1(M390R/M390R) mice have significantly delayed wound closure. In line with this, we provide data suggesting that BBS1(M390R/M390R) fibroblasts have impaired platelet-derived growth factor-AA (PDGF) receptor-alpha signaling, a key regulator of directional cell migration acting as a chemoattractant during postnatal migration responses such as wound healing. In addition, we show that BBS1(M390R/M390R) fibroblasts have upregulated RhoA expression and activity. The relevance of RhoA upregulation is demonstrated by the ability of RhoA-kinase inhibitor Y27632 to partially rescue the migration defect of BBS1(M390R/M390R) fibroblasts cells. We also show that accumulation of RhoA protein in BBS1(M390R/M390R) fibroblasts cells is associated with reduction and inactivation of the ubiquitin ligase Cullin-3. Consistent with this, Cullin-3 inhibition with MLN4924 is sufficient to reduce migration of normal fibroblasts. These data implicate the BBSome in cell motility and tissue repair through a mechanism that involves PDGF receptor signaling and Cullin-3-mediated control of RhoA. |
