Uncoupling p38 nuclear and cytoplasmic functions and identification of two p38 phosphorylation sites on -catenin: implications for the Wnt signaling pathway in CRC models

Background Activation of the Wnt pathway has been linked to colorectal cancer (CRC). Previous reports suggest that Wnt3a can activate p38. Besides, p38 alpha feeds into the canonical Wnt/beta-catenin pathway by inhibiting GSK3 beta through phosphorylation. Recently, we identified p38 alpha as a new druggable member of beta-catenin chromatin-associated kinase complexes in CRC.Methods The functional relationship between p38 alpha and beta-catenin was characterized in CRC cells, patient-derived CRC stem cells, patient-derived tumor intestinal organoids, and in vivo models (C57BL/6-APC(Min/+) mice). The role of p38 alpha in beta-catenin transcriptional activity was assessed by pharmacological inhibition with ralimetinib.Results We used the GSK3 beta inhibitor TWS-119, which promotes the activation of Wnt signaling, to uncouple p38 alpha nuclear/cytoplasmatic functions in the Wnt pathway. Upon GSK3 beta inhibition, nuclear p38 alpha phosphorylates beta-catenin at residues S111 and T112, allowing its binding to promoter regions of Wnt target genes and the activation of a transcriptional program implicated in cancer progression. If p38 alpha is pharmacologically inhibited in addition to GSK3 beta, beta-catenin is prevented from promoting target gene transcription, which is expected to impair carcinogenesis.Conclusions p38 alpha seems to play a dual role as a member of the beta-catenin destruction complex and as a beta-catenin chromatin-associated kinase in CRC. This finding may help elucidate mechanisms contributing to human colon tumor pathogenesis and devise new strategies for personalized CRC treatment.