Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization

Abstract

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.

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

“…45,46 The Ena/VASP proteins are thought to play redundant roles in regulating actin cytoskeletal dynamics (reviewed by Renfranz and Beckerle 47 ). Interaction between FAT and Ena/VASP proteins is mediated via an EVH1 domain.…”

“…45,46 This interaction is mediated via an EVH1 domain. All bipolar disorder-associated SNPs fall within an 8.7 kb LD block of FAT, which encodes the EVH1 domain of the FAT protein.…”

Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin

“…The cytoplasmic domain of FAT1 binds to β-catenin and plays a pivotal role in cell migration, polarization and morphogenesis (3,(10)(11)(12)(13)(14)(15)(16). Therefore, the deletion of this gene could implicate the characteristics and biological behavior of OSCCs that involve cell adhesion, migration and/or invasion, which might result in poor prognosis.…”

“…This gene product (hFAT1 protocadherin: FAT1) regulates actin dynamics, cell to cell contact and cell polarity and associate with Ena/VASP, Homer 3, and β-catenin (1)(2)(3). On the other hand, FAT1 is involved in the structure and function of the glomerular slit by podocytes (4), and the development of the brain as well as its function, especially regarding its association with the susceptibility to bipolar affective disorder (5,6).…”

Sequence and Structural Determinants of Strand Swapping in Cadherin Domains: Do All Cadherins Bind Through the Same Adhesive Interface?

“…Type I and type II, or classical, cadherins are cell-cell adhesion molecules that are present only in vertebrates, as are the closely related desmosomal cadherins, desmocollins and desmogleins. Other cadherin families include the clustered protocadherins, which appear only in vertebrates and regulate neuronal connectivity 5 ; invertebrate cadherins such as the Drosophila melanogaster DE-and DN-cadherins, which are known to have an adhesive function 6,7 ; the Dachsous and Fat families, which are present in vertebrates and invertebrates and appear to play a role in defining cell polarity [8][9][10][11] ; and the seven-pass transmembrane flamingo cadherins, which are also present in both vertebrates and invertebrates and appear to regulate cell polarity 12 . Our focus in this work is on the nature of the adhesive interface formed between cadherin molecules.…”