| DIAPH1, also termed diaphanous‑related formin 1, is a Rho‑effector formin that acts as an actin nucleation and elongation factor and is required for the assembly and maintenance of F‑actin structures such as actin cables and stress fibers that support cell shape, contractility, and migration. The protein contains N‑terminal GTPase‑binding, DID, and coiled‑coil regions and C‑terminal FH1, FH2, and DAD motifs, which together mediate autoinhibition and its release by activated RhoA, allowing the FH2 domain to bind barbed ends of actin filaments while the proline‑rich FH1 region recruits profilin–actin complexes to drive filament elongation. DIAPH1 localizes to the cortex, stress fibers, and cytokinetic structures, where it controls actin filament growth and stabilizes F‑actin, and it is also present at microtubule plus ends and the cell cortex as a scaffold that binds MAPRE1/EB1, APC, CLASP2, and MACF1 to couple microtubule capture and stabilization to cortical actin networks during cell migration and polarity establishment. RhoA‑dependent recruitment of DIAPH1 to membranes and its interaction with Src family kinases place it within signaling modules that coordinate actin remodeling with tyrosine kinase pathways, while the MEMO1–RHOA–DIAPH1 axis links ERBB2 activation to microtubule stabilization at the cell cortex through regulation of GSK3β activity and cortical targeting of APC and CLASP2. DIAPH1 also functions in the nucleus, where it promotes nuclear actin polymerization and supports serum‑dependent activation of the SRF–MRTFA transcriptional program, providing a direct connection between cytoskeletal dynamics and transcriptional control of cytoskeleton‑responsive genes. In endocrine cells, DIAPH1 participates in cAMP‑regulated trafficking and mitochondrial positioning, as cAMP–ERK–dependent phosphorylation of DIAPH1 modulates its stability and binding to partners such as kinesin, dynamin‑1, oxysterol‑binding proteins, actin, and β‑tubulin, which adjust organelle movement along actin and microtubule tracks during hormone production. Across tissues, DIAPH1 plays essential roles in cytokinesis, neurite outgrowth, brain development, and control of overall cell morphology and cytoskeletal organization, and it contributes to specialized actin architectures in hair cells of the inner ear, where disruption of DIAPH1 associates with autosomal dominant sensorineural hearing loss. In the liver, DIAPH1 supports myofibroblastic activation of hepatic stellate cells by regulating Rab5a activity and TGFβ receptor endocytosis, linking this formin to profibrotic TGFβ signaling and cytoskeleton‑dependent endocytic trafficking in fibrogenic responses. Elevated DIAPH1 expression in several cancers, including head and neck squamous cell carcinoma, associates with reduced apoptosis via ATR/p53‑related mechanisms and with enhanced adhesion and motility, indicating that DIAPH1‑driven coordination of actin–microtubule networks and signaling complexes contributes to malignant cell survival and invasive behavior. |
