Kelch-like family member 14 (KLHL14)

Kelch-like family member 14 (KLHL14) is a protein-coding gene encoding a substrate-binding subunit of the Cullin-RING ligase 3 (CRL3) ubiquitin ligase complex. KLHL14 contains BTB/POZ, BACK, and kelch-repeat domains, enabling its interaction with target proteins for ubiquitin-mediated degradation. It is expressed in multiple tissues, especially thyroid and lymphocytes, and functions in maintenance of cell differentiation, regulation of apoptosis, and modulation of immune cell signaling. KLHL14 acts as a tumor suppressor in various cancers including thyroid carcinoma, diffuse large B-cell lymphoma, and malignant mesothelioma, with loss-of-function mutations promoting cell survival and proliferation via the NF-κB pathway. In ovarian and endometrial cancers, KLHL14 is upregulated and correlates with poor prognosis, possibly due to its effects on cell proliferation, migration, and mTOR/WNT/TGF-beta signaling. KLHL14 also interacts with TorsinA in neurons and plays a role in lymphocyte development. Drugs such as ibrutinib target the downstream effects of KLHL14 loss in certain lymphomas. KLHL14 is a proposed biomarker for patient stratification and monitoring in some cancers. Therapeutic targeting must consider tissue-specific roles to avoid adverse effects on normal cell function.

Other names

Kelch-like protein 14KIAA1384PrintorProtein interactor of torsinAprotein interactor of Torsin-1AprintorKLHL14

Ubiquitin ligase activity promoting degradation of BCR subunits (IgM, CD79A, CD79B), reduces BCR signaling and cell survival in B-cell lymphomas. Loss of function increases BCR-dependent NF-κB signaling and survival. In ovarian cancer, high KLHL14 promotes proliferation and migration, suggesting a different regulatory network.