Sci Transl Med. 2025 Dec 10;17(828):eadu8484. doi: 10.1126/scitranslmed.adu8484. Epub 2025 Dec 10.
ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is essential for cell signaling in response to extracellular stimuli, and its overactivation is a hallmark of inflammation and tumorigenesis. The differential mechanisms underlying the physiological and pathological regulation of STAT3 remain elusive. Here, we demonstrated that cryptic splice sites in STAT3 generated heterogeneous isoforms with or without a single amino acid Ser701 (wS701/ΔS701), with the latter being more abundant in colon cancers. Intrinsic S701 underwent reversible phosphorylation catalyzed by mechanistic target of rapamycin complex 1 (mTORC1) and protein phosphatase 2A (PP2A). Upon inflammatory stimulation, phosphorylation at S701 (p-S701) sequestered Y705 phosphorylation (p-Y705) by interfering with the access of Janus kinase 1/2 and restricting STAT3 overactivation. In contrast, the STAT3_ΔS701 isoform was hyperactive because of the absence of this self-restricting mechanism. Deletion of S701 in mice increased susceptibility to colonic inflammation and tumorigenesis. Pharmacological inhibition of PP2A sustained p-S701 and alleviated colon inflammation in wild-type but not in ΔS701 mice. Our findings highlight the importance of STAT3 heterogeneity in colonic inflammation and colorectal cancer.
PMID:41370399 | DOI:10.1126/scitranslmed.adu8484