Table 1.
FLNC binding partners.
| Binding Partner | Binding Domain on FLNC | Function | Reference |
|---|---|---|---|
| HSPB1(HSP27) |
R18-21 | HspB1, an abundant molecular chaperone and FLNC form a complex. Phosphorylation of HspB1 facilitates extension of FLNC being localized to load-bearing sites. | [60] |
| MEK1/2 ERK1/2 |
Co-IP | FLNC enhances the mitogen-activated protein kinase signaling pathway during tumorigenesis. | [61] |
| Klhl31 | Co-IP | Klhl31 targets Flnc for ubiquitination and degradation. | [62] |
| HSPB7 | R24 | Aggregation and mislocalization of FLNC occur in the muscle by loss of HspB7, leading to myopathy. | [63] |
| KCNE2 |
Y2H, Co-IP | FLNC and KCNE2, potassium voltage-gated channel, co-localized within the cell, however, a physical interaction was only observed under hypoxic conditions. | [64] |
| α2C-adrenoceptors | 1979 and 2206 (R18-R20) In silico modeling |
Phylogenetic and sequence analysis showed that these interactions have evolved in warm-blooded animals. | [65] |
| Aciculin | Co-IP, SPR (R18-21) |
Dystrophin-binding protein aciculin interacts FLNC and Xin in Z-line. | [66] |
| Fbxl22 | Co-IP | FLNC is ubiquitinated in Fbxl22-dependent fashion. | [67] |
| Ankyrins-G | R5-6 | Ankyrins-G contains the muscle-specific Obscurin/Titin-Binding-related Domain that binds to FLNC and plectin. | [68] |
| Myopodin (synaptopodin2) | R20-21 | Myopodin also interacts with other Z-line proteins such as alpha-actinin and zyxin. The interaction might play a role in early assembly and stabilization of the Z-disc. | [43] |
| IGFN1 | R19-24 (Y2H) | FLNC interacts IGFN1 and KY at Z-line | [69] |
| MKK4 MKK7 |
Co-IP | MKK4 and MKK7 bind all FLNs. FLNA enhances the activation of MKK7 and JNK. | [70] |
| BAG3 | Co-localization | BAG-3 stimulates the release of filamin from a cytoskeleton. Released filamin could subsequently be ubiquitylated by the CHIP/UbcH5 conjugation machinery in the presence of the E1 ubiquitin-activating enzyme. FLNCW2710X blocks BAG3 mediated clearance of protein aggregates. |
[14,71] |
| CAP (SORBS1, Ponsin) | R2 | Cbl-associated protein (CAP) is enriched in oxidative muscle fiber. When overexpressed, CAP recruits FLNC to cell-extracellular matrix adhesions and inhibits FLNC-induced cell spreading on fibronectin. | [44] |
| USP25m | Y2H | The ubiquitin-specific protease USP25 interacts with three sarcomeric proteins. | [72] |
| Titin | R20-R24 (Y2H) | Titin Z2-Zis1 domain interacts FLNA/C, alpha-actinin, and nabulin. | [73] |
| Calpain 1 | R23-R24 | Calpain 1 cleaves FLNC hinge-2. Phosphorylation of FLNC by PKC alpha protects the proteolysis of FLNC by calpain 1. | [74] |
| Xin (XIRP1, 2) | R20 (Y2H) | Xin isoforms associate differentially with FLNC. XinB and FLNC compete for binding to aciculin and no ternary complex is formed. |
[45,66] |
| β-arrestin2 |
R22 (Y2H) | The interaction might regulate dopamine D3 receptor signaling. | [75] |
| RasGAP | R15-R17 | Disrupting the RasGAP-filamin pathway results in reduced myocyte growth. | [76] |
| Integrin beta1A | R20 (Y2H) | [39] | |
| PKBalpha |
substrate | PKBalpha phosphoarylate FLNC Ser2213, which lies in an insert not present in the FLNA and FLNB isoforms. Insulin also induced the phosphorylation of FLNC at Ser2213 in cardiac muscle in vivo |
[77] |
| KY protein | R20-R22 (Y2H) | KY protein cleaves FLNC. Mutation of KY protein disrupts normal distribution of FLNC. | [78] |
| alpha1-adrenergic receptor | Y2H | Biological significance of the interaction is not known. | [79] |
| Calpain 3 | substrate | FLNC after C3 cleavage, abolishes this interaction with the sarcoglycans. | [80] |
| N-RAP | R20-24 (Y2H) | During myofibril assembly in cultured chick cardiomyocytes, N-RAP, and filamin appear to co-localize with alpha-actinin in the earliest myofibril precursors found near the cell periphery, as well as in the nascent myofibrils that form as these structures fuse laterally. | [81] |
| FLNB | R24 | Heterodimer formation through R24 is possible between FLNC and B but not between FLNA and the other two filamins. | [33] |
| LL5beta | Co-IP | LL5beta binds PI(3,4,5)P3 | [82] |
| PKCalpha | R23-24 (Y2H) | Phosphorylates filamins | [83] |
| Migfilin | R21 | Migfilin interacts with Mig-2 and filamin at cell-matrix adhesion site and regulate cell shape change. | [84,85] |
| SHIP-2 (INPPL1) | R22-23 (Y2H and Co-IP) | Filamin-dependent SHIP-2 localization critically regulates phosphatidylinositol 3 kinase signaling to the actin cytoskeleton. | [86] |
| Myozenin-1, 2, 3 (FATZ, Calsarcins) | R19-24 (Y2H) | Myozenin interacts with FLNC and alpha-actinin in skeletal muscle Z line. | [39,40,41,42] |
| KCND2 | R20-24 (Y2H) | Filamin is required for Kv4.2 localize at filopodial roots. | [87] |
| Myotilin | R20 (Y2H) | Insertion of 82 amino acid residue in R20 defines specific localization of FLNC at Z-line and this domain interacts with myotilin. | [7] |
| γ-, δ-Sarcoglycans | R20-R24 (Y2H) | The identification of FLNC isoform in muscle. | [5,39] |
| Actin | Predicted from sequence similarity and localization in cells. | High homology to actin-binding domains of FLNA and B. | [5] |
Co-IP, Co-immunoprecipitation; Y2H, yeast two hybrid; SPR, Surface plasmon resonance; SPPBA, Solid-phase protein-binding assays.