The filamins

Figures & data

Figure 1 A schematic structure of FLNa molecule and the F-actin crosslink. This model was generated on PyMOL (www.pymol.org) by assembling Ig domains uploaded on protein data bank and by fitting them within rotary shadowed images of FLNa molecules. Structures were modeled using the Swiss model database (http://swissmodel.expasy.org). Rotary shadowed images of full-length FLNa and its subfragments are adopted from reference 12. The atomic structure of IgFLNa24 was generated on PyMOL (PDB accession number: 3CNK).

Figure 2 Atomic structures of FLNa rod 2 subdomains and the binding interfaces of known FLNa-partner complexes. The models were generated on PyMOL (PDB accession number: IgFLNa16–17, 2K7P; IgFLNa20–21, 2J3S; IgFLNa18–19, 2K7Q; IgFLNa17-GPIbβ, 2BP3; IgFLNa21-integrinβ7, 2BRQ). The CD faces of repeats and strand A are indicated with blue and red, respectively.

Figure 3 Model for how mechanical force regulates FLNa-partner interactions. Mechanical force changes the conformation of the rod 2 domain to release partner A by changing the geometry between the two FLNa subunits, while exposing the cryptic binding for partner B by unfolding the A strand interaction between repeats 20 and 21.

Figure 4 Schematic of how certain FLN-partner complexes regulate cell adhesion and motility. Top part: FLN crosslinks actin filaments and attaches them to signaling molecules, membrane proteins and the extracellular matrix through adhesion molecules such as integrins. FLN is required for the recycling, trafficking and stabilization of membrane proteins. FLN also scaffolds multiple partners in close proximity on rod 2, thereby facilitating signal transduction at specific locations within cells. Note that the expression levels of FLN-binding partners are dependent on the cell type and, therefore not all partners necessarily participate in cell adhesion and migration in the same cell. Bottom part: Model for how FLN regulates integrin activation. FLN acts as a negative regulator for integrin activation by blocking talin binding to the β integrin tail. Perturbation of this interaction allows talin to interact with β integrin, thereby activating integrin at the leading edge of a migrating cell.

Table 1 Filamin binding partners involved in cell adhesion, spreading and migration

Partners	Binding sites*	Significance
F-actin	ABD, rod-1	FLN induces orthogonal F-actin networks with unique mechanical and physiological properties1,12
Calmodulin	ABD	Regulates F-actin binding in vitro95
R-Ras	3	Enhances integrin activation98
Syk	5	Flna is required for ITAM-mediated receptor signaling in platelet99
Vimentin	1–8	Expression of IgFLNa1-8 restores spreading of filamin-deficient HEK-293 cells, vimentin phosphorylation, and the cell surface expression of β1 integrins90
Supervillin	8–10, 20–22	Overexpression of IgFLNa8–10, but not 20–22 decreases spreading of Hela cells on fibronectin100
Pro-Prion	10,16–18, 20, 21, 23	FLNa interacts with the GPI anchor peptide signal sequence of pro-PrP that is expressed in some cancer cells This interaction also promotes cell spreading and migration of melanoma cells22,101
FAP52(PASCIN2/Syndapin II)	15–16	Formation of focal adhesion102
ECSM2	15–16, 19–21	Endothelial chemotaxis and tube formation103
FILIP	15–18	Downregulates FLNa and controls polarity and migration of neocortical cell104
GPIbα (CD42b)	17(A/B)	Platelet adhesion and activation Genomic instability15,105,106
ICAM-1	19–24(A/B)	Transendothelial migration No binding to splice variant-1107
Integrin β	21 (A/B/C)	Adhesion Mechanoprotection Negative regulation of integrin activation16, 47
Migfilin (FBLP-1)	21 (A/B/C), 10–13 (B)	Disconnects FLNa from integrin and promotes talin-integrin binding17,18,108,109
Sphingosine kinase 1	22–24	FLNa-dependent kinase activity110
Tissue Factor	22–24	Phosphorylation of TF enhances the interaction111
CEACAM1 (CD66a)	23–24	Reduces cell migration112
Trio	23–24	GEF for RhoG/Rac1 and RhoA Required for ruffling82
FilGAP	23 (A specific)	Rho- and ROCK-regulated GAP for Rac. FLNa-binding is required for cell spreading and stimulates GAP activity19,96
Rho	24	Remodeling of cytoskeleton113
Rac	24 (B: 20–21)	Remodeling of cytoskeleton113–115
Cdc42	24	Remodeling of cytoskeleton113
RalA	24	Filopodia formation113
ROCK	24	Remodeling of cytoskeleton116
FILIP-1L (downregulated in ovarian cancer 1)**	?	Overexpression of FILIP1L inhibits cell proliferation and migration and increased apoptosis117
IKAP (ELP1)	?	Loss-of-function mutations in the IKBKAP gene, which encodes IKAP, cause familial dysautonomia118
Lbc**	?	RhoGEF Co-immunorecipitated with calcium-sensing receptor, RhoA, and Gαq119
P190RhoGAP**	?	Expression of calpain-insensitive FLNa excludes p190RhoGAP from the lipid raft, thereby increase Rho activity46
Vav-2**	?(B)	Guanine nucleotide exchange factor for the Rho family Complexes with Rac-1114
p311**	?	Highly expressed in invasive glioma cells and enhances glioma cell migration120

* Binding site on FLNa from N-terminal (top) to C-terminal (bottom) unless otherwise noted,

** direct interaction has not been confirmed, cytoskeleton (red), small GTP-binding proteins and their regulators (yellow), kinases (green), transmembrane proteins (cyan), others (white).

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