Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization.
Cell migration requires integration of cellular processes resulting in cell polarization and actin dynamics. Previous work using tools of Drosophila genetics suggested that protocadherin fat serves in a pathway necessary for determining cell polarity in the plane of a tissue. Here we identify mammalian FAT1 as a proximal element of a signaling pathway that determines both cellular polarity in the plane of the monolayer and directed actin-dependent cell motility. FAT1 is localized to the leading edge of lamellipodia, filopodia, and microspike tips where FAT1 directly interacts with Ena/VASP proteins that regulate the actin polymerization complex. When targeted to mitochondrial outer leaflets, FAT1 cytoplasmic domain recruits components of the actin polymerization machinery sufficient to induce ectopic actin polymerization. In an epithelial cell wound model, FAT1 knockdown decreased recruitment of endogenous VASP to the leading edge and resulted in impairment of lamellipodial dynamics, failure of polarization, and an attenuation of cell migration. FAT1 may play an integrative role regulating cell migration by participating in Ena/VASP-dependent regulation of cytoskeletal dynamics at the leading edge and by transducing an Ena/VASP-independent polarity cue.
Moeller
Marcus J
MJ
Institute for Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany.
Soofi
Abdulsalam
A
Braun
Gerald S
GS
Li
Xiaodong
X
Watzl
Carsten
C
Kriz
Wilhelm
W
Holzman
Lawrence B
LB
D000199:Actins / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity; D003599:Cytoskeleton / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D014945:Wound Healing
D000199:Actins; D015820:Cadherins; D015815:Cell Adhesion Molecules; C102177:Evl protein, mouse; C502403:FAT1 protein, human; D007074:Immunoglobulin G; D034741:RNA, Small Interfering; C502406:fat1 protein, mouse