Disease relevance of FLNC

• The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy [1].
• In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM, we identified a co-segregating, heterozygous nonsense mutation (8130G-->A; W2710X) in the filamin c gene (FLNC) on chromosome 7q32 [2].
• To approach this problem in vivo, we used the human melanoma cell, M2, which lacks actin-binding protein-280 (ABP-280) and forms membrane blebs, which are not seen in wild-type or ABP-transfected cells [3].
• These results suggest that KY is an intrinsic part of the protein networks underlying the molecular mechanism of several limb-girdle muscular dystrophies, particularly those where interactions between filamin C and disease causing proteins have been shown [4].
• The rearrangements are due to insertion of a deleted Moloney murine leukemia virus (Mo-MLV) provirus in the 5' region of the c-myb gene and thus are similar to rearrangements in the ABPL tumors (G. L. C. Shen-Ong, M. Potter, J. F. Mushinski, S. Lavu, and E. P. Reddy, Science 226:1077-1080, 1984) [5].

High impact information on FLNC

• The ABPL tumors were examined for the expression of other oncogenes that may be associated with their transformed state, in the absence of transforming virus [6].
• Furthermore, alternative splice variants of filamin-B and filamin-C, from which the flexible hinge-1 region is deleted (DeltaH1), were induced during in vitro differentiation of C2C12 mouse myoblasts [7].
• 1. The mutation is the first found in FLNC and is localized in the dimerization domain of filamin c. Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly [2].
• Myozenin: an alpha-actinin- and gamma-filamin-binding protein of skeletal muscle Z lines [8].
• To better understand the structure and function of Z lines, we used sarcomeric isoforms of alpha-actinin and gamma-filamin to screen a human skeletal muscle cDNA library for interacting proteins by using the yeast two-hybrid system [8].

Chemical compound and disease context of FLNC

• The Pichia expressed protein reacted weakly with IgE, but strongly with IgG of ABPA sera compared to E. coli expressed Asp f 2 [9].

Biological context of FLNC

• FLNC is divided into 48 exons and 47 introns and covers approximately 29.5 kb of genomic DNA [10].
• Two principal forms of the actin binding protein, filamin, are expressed in mammalian cells: nonmuscle and muscle isotypes (FLN-1 and FLN-2) [11].
• ABPL has a unique insertion sequence of 82 amino acids in repeat 20 that was not present in the other two homologues and has a tissue distribution that was also different from the other two homologues [12].
• Previous computer analyses suggested two possible lipid binding sites, residues 49-71 and 131-155, of the primary amino acid sequence on ABP-280 (filamin), which could facilitate membrane attachment/insertion [13].
• Phosphorylation of filamin (ABP-280) regulates the binding to the lipid membrane, integrin, and actin [14].

Anatomical context of FLNC

• Northern and Western blots showed that both, ABP-L/gamma-filamin mRNA and protein, are absent from proliferating cultured human skeletal muscle cells [15].
• Stimulation of PKC activity in myotubes, prevented gamma-filamin proteolysis by calpain and resulted in an increase in myotube adhesion [16].
• Calpain 1-gamma filamin interaction in muscle cells: a possible in situ regulation by PKC-alpha [16].
• Filamin C may be involved in reorganizing the cytoskeleton in response to signalling events and in muscle it may, in addition, fulfill structural functions at the Z-disk [17].
• On the one hand, filamin C is associated with the Z-disk of the myofibrillar apparatus and binds to myotilin; on the other hand, it interacts with the sarcoglycan complex at the sarcolemma [17].

Associations of FLNC with chemical compounds

• We also located the binding domains in the C-terminus of gamma-filamin with a cleavage site between serine 2626 and serine 2627 in the hinge 2 region [16].
• In this study, actin-binding protein 280 (ABP-280), a widely expressed cytoskeleton-associated protein that plays an important role in regulating cell morphology and motility, was found to associate with the third cytoplasmic loop of dopamine D(2) receptors [18].
• Phosphorylation of actin-binding protein (ABP-280; filamin) by tyrosine kinase p56lck modulates actin filament cross-linking [19].
• We have cloned and sequenced a 9.4-kilobase cDNA specifying a new 280-kDa protein interacting with the cytoplasmic tail of glycoprotein (Gp) Ibalpha and showing considerable homology to actin-binding protein 280 (ABP-280) and chicken retinal filamin [20].
• To elucidate the immunoglobulin E (IgE) binding epitopes in the linear sequence of Asp f 2, we synthesized decamer peptides spanning the whole molecule of Asp f 2 on derivatized cellulose membranes and evaluated IgE binding in ABPA patient and control sera [21].

Other interactions of FLNC

• To improve candidate gene cloning approaches, FLNB was precisely mapped at 3p14 in an interval of 0.81 cM between WI3771 and WI6691 and FLNC at 7q32 in an interval of 2.07 cM between D7S530 and D7S649 [10].
• This interaction could co-localize heterologously expressed gamma-filamin with GFP-LL5beta in the unidentified vesicles [22].
• In contrast, ACTA1 and FLNC appear to be stable proteins, indicating that their interaction with USP25m is not related to their turnover rate [23].
• In all three conditions, the immunoreactivity in the cores for filamin C was considerably stronger than that for desmin [17].
• A growing family of Arp2/3 complex activators such as the WASP family, type I myosins, and the newly identified activators cortactin and Abplp tightly regulate this activity within the cell [24].

Analytical, diagnostic and therapeutic context of FLNC

• The yeast two-hybrid method was used to identify possible binding partners for the insert-bearing Ig-like domain 20 of gamma-filamin [25].
• Molecular cloning of human ABPL, an actin-binding protein homologue [12].
• An isoform of ABPL lacking Hinge I, with a calculated molecular mass of 286 kDa, was also identified by the reverse transcriptase PCR (RT-PCR) method [12].
• Mechanical unfolding of single filamin A (ABP-280) molecules detected by atomic force microscopy [26].
• Cloning, expression, purification, crystallization and preliminary crystallographic analysis of gamma-filamin repeat 23 [27].

References