Systematic Characterization of Cancer-Associated SPOP Mutants Reveals Novel and Reprogrammable Degradative Activities.

ABSTRACT: Speckle-type POZ protein (SPOP) functions as the substrate adaptor of the Cullin3-RING ligase complex and is recurrently mutated in multiple cancer types. Among these, F102C and F133L are frequent prostate cancer mutations within the substrate-binding domain, yet their biochemical consequences remain incompletely understood. Using quantitative proteomics, we show that SPOP-F133L, unlike SPOP-F102C, retains degradative activity toward the nuclear basket proteins NUP153 and TPR, indicating substrate-dependent loss-of-function. Moreover, SPOP-F133L induces partial down-regulation of p53 through a Cullin-RING ligase-dependent, post-translational mechanism, revealing a potential neo-substrate relationship. Finally, we demonstrate that both SPOP-F102C and SPOP-F133L support targeted protein degr

SUBMITTER: Caldwell AG 

PROVIDER: S-EPMC12802387 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature