Protein diaphanous homolog 3 (DIAPH3) (DIAPH3)

Protein diaphanous homolog 3 (DIAPH3), commonly referred to as mDia2 in mammalian studies, is a member of the Diaphanous-related formin (DRF) family and a key effector of Rho GTPases [1.2.1, 1.3.1]. It functions as a cytoskeletal regulator by nucleating and elongating unbranched actin filaments and stabilizing microtubules, which are essential for processes such as cytokinesis, cell motility, and filopodia formation [1.3.1, 1.4.2]. In oncology, DIAPH3 is frequently dysregulated; its loss is linked to the formation of large oncosomes and increased metastasis in prostate cancer, while its overexpression correlates with poor prognosis in glioblastoma and pancreatic cancer [1.4.1, 1.4.5]. The protein is considered a promising therapeutic target, with small-molecule inhibitors like SMIFH2 targeting its FH2 domain to block actin assembly [1.1.4]. Conversely, agonists known as intramimics (e.g., IMM-01 and IMM-02) have been developed to disrupt its autoinhibitory mechanism, offering a strategy to inhibit tumor cell invasion by over-activating cytoskeletal dynamics [1.2.1, 1.2.3]. However, therapeutic application faces challenges such as potential cytotoxicity and the risk of inducing aneuploidy due to DIAPH3's critical role in mitotic spindle assembly [1.4.1, 1.4.3].

Other names

mDia2Diaphanous-related formin 3DRF3DIA2hDia2

Inhibition of the FH2 domain to prevent actin assembly (antagonism) or disruption of the autoinhibitory DID-DAD interaction to constitutively activate the protein (agonism) [1.1.4, 1.2.1].