Abstract

TMEM121 is a six-pass transmembrane protein consisting of an N-terminal transmembrane domain (TD; residues 1-284) and a C-terminal polyproline sequence (PP; residues 284-319). In this study, publicly accessible databases were utilized to ascertain that TMEM121 correlates with various cytokines associated with the MAPK signaling pathway in cervical cancer. Furthermore, TMEM121 expression was negatively correlated with ERK expression in cervical cancer tissues. Protein interaction prediction using AlphaFold3 suggested an interaction between TMEM121 and ERK1/2, which was experimentally validated through Co-immunoprecipitation and immunofluorescence analyses. Both full-length TMEM121 and the TD truncator interacted with ERK and downregulate p-ERK1/2 protein levels, thereby inhibiting the proliferation and invasion of cervical cancer cells. In contrast, the PP truncator did not exhibit these effects. RNA-seq analysis further confirmed a significant association between TMEM121 and the MAPK signaling pathway in cervical cancer. Additionally, flow cytometry analysis showed that the ERK inhibitor PD98059 reversed the S phase cell cycle arrest induced by TMEM121 overexpression. Collectively, these findings suggest that TMEM121 exerts its inhibitory effects on the growth, proliferation, and invasion of cervical cancer cells through its interaction with ERK, providing a theoretical basis for the development of novel diagnostic and therapeutic strategies for cervical cancer.