Filamins in cell signaling, transcription and organ development Alex-Xianghua Zhou 1, 2 , John H. Hartwig 3 and Levent M. Akyu ¨ rek 1, 2 1 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Go ¨ teborg, Sweden 2 The Wallenberg Laboratory for Cardiovascular Research, University of Gothenburg, SE-415 45 Go ¨ teborg, Sweden 3 Division of Translational Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin filament networks and link them to cellular membranes where they integrate cell architectural and signaling functions important for cell locomotion. Filamins have been shown to bind to proteins with diverse functions and are implicated in human genetic diseases including malformations of the skeleton, brain, and heart. Mouse models of filamin deficiency have advanced our understanding of the important roles filamins play in embryonic development and disease progression. These studies provide clear evidence that cytoskeletal filamin proteins integrate cell signaling, transcription and organ development. This review focuses on the emerging roles of filamins in cell signaling and transcription, with emphasis on cell moti- lity and organ development. Introduction The actin cytoskeleton is not only essential for the for- mation and maintenance of cell shape but is also required for the regulation of cell morphology and locomotion in response to external stimuli. Its dynamic remodeling is mediated by a large number of actin-binding proteins (ABP) including filamins. The filamin family consists of three homologous proteins (FLNA, FLNB, and FLNC) that are products of different genes and their mRNA splice variants (Box 1). Filamins stabilize cortical three-dimen- sional F-actin networks and link them to cellular mem- branes by binding to transmembrane receptors or ion channels [1]. The mechanical properties of filamins gen- erate dynamic orthogonal F-actin networks, thereby con- ferring membrane integrity and defending cells against mechanical stress (Box 2). In addition to F-actin, filamins bind to 70 diverse cellular proteins [2] including trans- membrane receptors and signaling molecules, providing essential scaffolding functions and integrating multiple cellular behaviors (Figure 1). Due to the many functions of filamins in humans, deleterious mutations in filamin genes cause a wide range of developmental malformations of the brain, skeleton, and heart [3] (Box 3). Here we review the latest findings on cell signaling pathways regulated by filamins to gain a more comprehensive understanding of their functions. We then discuss how recently developed mouse models of filamin deficiency advance our knowledge on the roles of filamins in human organ development and disease progression. Filamins in cell motility Directed cell movement is essential for both embryonic development and homeostasis. Aberrant unregulated migration leads to pathological processes including vascu- lar disease, chronic inflammatory disease, and tumor for- mation and metastasis. Filamins are positioned at both the leading edge and the rear of polarized motile cells where they influence the nature of cytoplasmic protrusions and retractions by directly regulating actin cytoskeleton remo- deling. The spatial distribution, level of expression, and even the modulation of filamin–actin binding interactions could contribute to stabilization and remodeling of cortical F-actin during cell motility. Thus, the existence of filamins at the leading edge, or the cell rear, results in collections of interacting partner proteins at the membrane sites where migration is initiated or terminated. Filamins and integrin signaling The ability of adhesion receptors to transmit biochemical signals and bear mechanical forces across cell membranes depends on their interactions with the underlying F-actin cytoskeleton. Filamins are well-positioned in cells to affect matrix–cytoskeleton signaling by virtue of binding to both F-actin and the cytoplasmic tails of membrane receptors such as the b-chains of the major transmembrane adhesion receptors, the integrins. These interactions are now under- stood at the atomic level. Filamin repeats are b-barrel structures composed of 8 b-sheet strands (A–H). A groove is generated between the C and D strands into which the opposing b-integrin site fits. This interaction, when recon- stituted with one repeat, is of micromolar affinity and is insufficient to promote a stable complex: both subunits of filamin must therefore engage b-integrin chains for phys- iological results. However, the filamin–integrin interaction has greater complexity. The C-terminal (C-T) repeats (repeats 16–23) of FLNA have newly recognized inter- repeat interactions that are not found in the N-terminal (N-T) repeats (1–15) because the C-T b-sheet strands of neighboring repeats can fold out from its b-barrel structure to interact with another repeat. This structure generates cryptic sites on filamin that can be opened by conformation changes induced by either mechanical stretch or by the binding of other partner proteins. For example, the primary binding site of integrin on filamin repeat 21, that Review Corresponding author: Akyu ¨ rek, L.M. (levent.akyurek@gu.se). 0962-8924/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2009.12.001 Available online 12 January 2010 113