Kelch-like protein 18 (KLHL18)

Kelch-like protein 18 (KLHL18) is a member of the Kelch-like family of BTB-BACK-Kelch domain–containing proteins that acts as a substrate adaptor within CUL3-containing E3 ubiquitin ligase complexes[1][4]. KLHL18 promotes the ubiquitination and subsequent degradation of specific substrate proteins—most notably the PI3K regulatory subunit p85α (PI3Kp85α) and AURKA kinase—thereby modulating key cell signaling and cell cycle pathways. In cancer, especially non-small cell lung cancer, KLHL18 is downregulated and functions as a tumor suppressor: its increased expression leads to decreased PI3K/Akt/mTOR signaling, reduced PD-L1 protein (and thus impaired tumor immune escape), and suppression of cell proliferation, migration, and invasion[2]. KLHL18 may also regulate protein localization in photoreceptors (demonstrated in mouse), and its human gene is associated with several syndromic conditions, though its pathophysiological role there is less defined[3][4][5]. No approved drugs are known to specifically target KLHL18.

Other names

KIAA0795OK/SW-cl.74FLJ13703kelch like family member 18

KLHL18 forms a complex with CUL3 (Cullin 3 RING E3 ubiquitin ligase) and functions as an adaptor, targeting specific substrates such as PI3K regulatory subunit p85α for ubiquitination and proteasomal degradation[2][4]. Regulates AURKA ubiquitination and activation at centrosomes, critical for mitotic entry[4].