Disease relevance of FHOD1

• FHOD1 proteins were stably expressed in WM35 melanoma cells and NIH-3T3 fibroblasts [1].

High impact information on FHOD1

• Simultaneous mutation of both motifs efficiently released autoinhibition of FHOD1 in NIH3T3 cells resulting in the formation of actin stress fibers and increased serum response element transcription [2].
• NMR structural analysis and size exclusion chromatography experiments revealed that the FHOD1 DAD is intrinsically unstructured with a tendency for a helical conformation in the hydrophobic autoregulation motif [2].
• Formin homology domain protein (FHOD1) is a cyclic GMP-dependent protein kinase I-binding protein and substrate in vascular smooth muscle cells [3].
• FHOD1 is highly expressed in human coronary artery, aortic smooth muscle cells, and in human arterial and venous endothelial cells [3].
• In glutathione S-transferase pull-down experiments, the FHOD1 C terminus (amino acids 964-1165) binds full-length PKGI [3].

Biological context of FHOD1

• Expression of a constitutive active FHOD1 variant in HeLa cells not only resulted in pronounced formation of FHOD1-actin fibers but also caused marked cell elongation and parallel alignment of microtubules without affecting cytokinesis of these cells [4].
• Formin homology-2-domain containing protein 1 (FHOD1) regulates gene transcription, actin-cytoskeleton structure, and cell migration [5].
• Here, we identified and characterized FHOD3 (also known as FHOS2), a novel gene homologous to FHOD1, by using bioinformatics [6].
• Cells expressing full-length FHOD1 demonstrated an elongated phenotype compared with vector-transfected cells and cells expressing a truncated FHOD1 (1-421) that lacks the conserved FH1 and FH2 domains [1].
• However, FHOD1-induced stress-fiber formation and gene expression from the skeletal actin promoter was independent of ERK activation [7].

Anatomical context of FHOD1

• Here we report that active FHOD1 also coordinates microtubules with these actin stress fibers [4].
• FHOD1 coordinates actin filament and microtubule alignment to mediate cell elongation [4].
• Furthermore, activated FHOD1 interfered with lamellipodia formation [8].
• These data demonstrate that FHOD1 interacts with and regulates the structure of the cytoskeleton and stimulates cell migration in an integrin-independent manner [1].
• Stable overexpression of full-length FHOD1 enhanced the migration of WM35 and NIH-3T3 cells to type-I collagen and fibronectin, respectively [1].

Associations of FHOD1 with chemical compounds

• These studies demonstrate that FHOD1 is a PKGI-interacting protein and substrate in VSMCs and show that cyclic GMP negatively regulates the FHOD1-PKGI interaction [3].
• Moreover, FHOD1 overexpression did not alter integrin usage during adhesion or migration [1].
• Overexpression of FHOS and FHOS78 resulted in enhanced insulin-stimulated glucose uptake in L6 cells to similar levels [9].

Co-localisations of FHOD1

• In addition, FHOD1 co-localized to lamellipodia with Raf-1 and to stress fibers with MEK [7].

Regulatory relationships of FHOD1

• These data suggest that FHOS induces transcription from SREs by multiple pathways and that Rac1 may influence the course of some FHOS-induced signaling events [10].
• Finally, using a run-on transcription assay we show that the C-terminal FHOD1 cleavage product has the ability to inhibit RNA polymerase I transcription when overexpressed in HeLa cells as shown by blockage of BrUTP incorporation [11].
• These results define a role for endogenous FHOD1 in SH4 domain-induced blebbing and suggest that its activity is regulated by ROCK1 in a Src-dependent manner [12].

Other interactions of FHOD1

• FHOD3 and FHOD1 showed 52.1% total-amino-acid identity [6].
• The proline-rich FH1 domain of FHOD1 was sufficient to interact with the central portion of PRKCP1 and full-length cyclophilin B [5].
• Intramolecular autoinhibitory interactions between the C terminus of FHOS and an N-terminal region partially overlapping the Rac1 interaction domain were also identified [10].
• These findings suggest that FHOS mediates an interaction between GLUT4/IRAP-containing vesicles and the cytoskeleton and may participate in exocytosis and/or retention of this membrane compartment [9].
• We show that formin homologue overexpressed in spleen (FHOS/FHOD1) binds the cytoplasmic domain of human CD21 through its C terminus [13].

Analytical, diagnostic and therapeutic context of FHOD1

• Here, we report the detection of homotypic interactions of FHOD1 in the yeast two-hybrid system, by co-immunoprecipitation and co-localization in mammalian cells [14].
• Immunofluorescence studies of human VSMC show that FHOD1 is cytoplasmic and is concentrated in the perinuclear region [3].
• Using confocal microscopy, we further demonstrate that while full length FHOD1 is mostly cytoplasmic, the FHOD1 N-terminal cleavage product is diffusely localized throughout the cytoplasm and the nucleoplasm, whereas the C-terminal cleavage product is almost exclusively nuclear with some nucleolar localization [11].
• Though widely expressed, FHOS RNA is most abundant in the littoral cell, a major constituent of the red pulp of human spleen believed to function in antigen filtration [13].

References