Protein diaphanous homolog 1 (Diaph1) (Diaph1)

Protein diaphanous homolog 1 (Diaph1), also known as mDia1 or DIAPH1, is a formin family protein that acts as an effector of Rho small GTPases, primarily regulating actin polymerization through its formin homology 1 (FH1) and FH2 domains. It nucleates actin filaments by binding actin dimers, facilitates filament elongation by recruiting profilin-bound G-actin to barbed ends, and protects against capping proteins, thereby controlling cell shape, motility, cytokinesis, and polarity. Diaph1 also stabilizes microtubules, promotes cell migration via scaffolding MAPRE1 and APC, and modulates endocytosis by interacting with receptors like TβRII and Rab5a, influencing intracellular trafficking. In disease contexts, Diaph1 drives hepatic stellate cell activation into myofibroblasts via TGFβ signaling, promoting liver fibrosis and tumor growth through paracrine factors; its inhibition suppresses these effects. Additionally, phosphorylation of Diaph1 at sites like Thr-759 by cAMP/ERK pathways regulates its stability, binding to partners like kinesin, actin, and ORP2, and mitochondrial movement critical for cortisol biosynthesis in adrenocortical cells. No approved drugs directly target Diaph1, but tool compounds like SMIFH2 inhibit its activity, highlighting therapeutic potential in fibrotic and oncogenic liver diseases despite challenges in cytoskeletal disruption.

Other names

mDia1DIAPH1diaphanous-related formin 1

Inhibition of Diaph1 formin homology 2 (FH2) domain to block actin nucleation and elongation, thereby disrupting Rho GTPase-mediated downstream effects on actin dynamics and endocytosis