title: Polycystin-1 regulates actin cytoskeleton organization and directional cell migration through a novel PC1-Pacsin 2-N-Wasp complex.
abstract: How epithelial cells form a tubule with defined length and lumen diameter remains a fundamental question in cell and developmental biology. Loss of control of tubule lumen size in multiple organs including the kidney, liver and pancreas features polycystic kidney disease (PKD). To gain insights into autosomal dominant polycystic kidney disease, we performed yeast two-hybrid screens using the C-terminus of polycystin-1 (PC1) as bait. Here, we report that PC1 interacts with Pacsin 2, a cytoplasmic phosphoprotein that has been implicated in cytoskeletal organization, vesicle trafficking and more recently in cell intercalation during gastrulation. PC1 binds to a 107-residue fragment containing the α3 helix of the F-BAR domain of Pacsin 2 via a coiled-coil domain in its C-tail. PC1 and Pacsin 2 co-localize on the lamellipodia of migrating kidney epithelial cells. PC1 and Pacsin 2-deficient kidney epithelial cells migrate at a slower speed with reduced directional persistency. We further demonstrate that PC1, Pacsin 2 and N-Wasp are in the same protein complex, and both PC1 and Pacsin 2 are required for N-Wasp/Arp2/3-dependent actin remodeling. We propose that PC1 modulates actin cytoskeleton rearrangements and directional cell migration through the Pacsin 2/N-Wasp/Arp2/3 complex, which consequently contributes to the establishment and maintenance of the sophisticated tubular architecture. Disruption of this complex contributes to cyst formation in PKD.
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Su
authors.forename: Vy
authors.initials: V
authors.lastname: Nguyen
authors.forename: Kristina
authors.initials: K
authors.lastname: Roberts
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Li
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takakura
authors.forename: Markus
authors.initials: M
authors.lastname: Plomann
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D051378:Actin-Related Protein 3 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D050396:TRPP Cation Channels / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*
chemical_list: D051378:Actin-Related Protein 3; D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D050396:TRPP Cation Channels; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C495928:ACTR3 protein, human; C120714:PACSIN2 protein, human; C495771:WASL protein, human