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doi: 10.1242/10.1242/jcs.00611

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Formins: signaling effectors for assembly and polarization of actin filaments

¹ Department of Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6
² Biology Department, University of Pennsylvania, Philadelphia, PA 19104-6018, USA
³ Banting and Best Department of Medical Research and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1L6

View larger version (75K): [in a new window]   Fig. 1. The branched actin networks found in fibroblast lamellipodia (A) and actin bundles in a bristle of Drosophila melanogaster (B) [Adapted with permission (Hudson and Cooley, 2002; Svitkina and Borisy, 1999)] (bar, 0.1 µm); a schematic diagram showing branched (C) and unbranched (D) actin filaments. The Arp2/3 complex (green) crosslinks and stabilizes branched filaments, whereas tropomyosin (purple) stabilizes unbranched filaments.

View larger version (18K): [in a new window]   Fig. 2. (A) Domain organization of the formin family of proteins. Shown is the formin-homology 1 (FH1) domain, the FH2 domain, which controls actin nucleation, and the FH3 domain, which is important for localization of some formins. (B) Domain organization of the Diaphanous-related formins (DRFs). Unique to this class of proteins is the regulatory Rho-binding domain (RBD), which binds activated forms of Rho GTPases and the Dia-autoregulatory-domain (DAD), which mediates an intramolecular auto-inhibitory interaction with RBD. An activated formin, with the DAD-RBD intramolecular interaction relieved by Rho-GTP binding, is shown.

View larger version (43K): [in a new window]   Fig. 3. Yeast formin proteins Bni1p and Bnr1p are specifically required for the assembly of actin cables but not actin patches. bnr1 bni1-ts (temperature-sensitive) mutants show normal actin cables at permissive temperatures (18°C) but rapidly lose cables at restrictive temperatures (34.5°C) with no effect on cortical actin patches.

View larger version (25K): [in a new window]   Fig. 4. Bni1p controls cell polarity in budding yeast through the assembly of actin cables. Bni1p is activated by Rho GTPases (1). Activated Bni1p nucleates and assembles actin cables (2). Tropomyosin stabilizes the growing cables (3). Bni1p binds to the barbed ends of cables, thereby establishing their polarity. In turn, the polarized cables can then serve as tracks for myosin V, Myo2p, which migrates towards the barbed end of the actin cable to deliver secretory vesicles (4) and to orient the mitotic spindle (5).

View larger version (42K): [in a new window]   Fig. 5. (A) Two different actin nucleators. Actin nucleation by FH2 occurs by dimer stabilization. Comparison between Arp2/3-mediated nucleation and FH2-mediated nucleation indicates that the Arp2/3 complex, in its activated state, is a more efficient nucleator since it only requires the addition of one monomer to create a stable nucleus. (B) The Arp2/3 complex (left panel, green ovals) nucleates a new filament on the side of a pre-existing filament at a 70° angle. The Arp2/3 complex also caps the slowing-growing end of the new filament and allows it to grow from its barbed end, ultimately generating a branched network that is crosslinked by the Arp2/3 complex. The FH2 domain (right panel, blue rectangle) of Bni1p nucleates an actin filament but stays associated with the barbed growing end, thereby regulating filament elongation. The filaments that form are unbranched, polarized by the FH2 domain and stabilized by tropomyosin (purple). (C) Model for how the FH1 domain and profilin-actin contributes to formin-induced nucleation of actin filaments. First, the FH1 domain localizes profilin, which sequesters an actin monomer, to the nucleation vicinity. The FH1 domain may cause profilin to release its bound actin, which the FH2 domain can then utilize to nucleate an actin filament. The filament elongates at the barbed end, a process that also requires profilin-actin.