TAK1-mediated phosphorylation of PLCE1 represses PIP2 hydrolysis to impede esophageal squamous cancer metastasis

TAK1, a serine/threonine protein kinase, has been identified as a key regulator in a wide variety of cellular processes. However, its function and involved mechanism in cancer metastasis are still not well understood. Here, we found that knockdown of TAK1 promoted esophageal squamous cancer cell (ESCC) migration and invasion, whereas overexpression of TAK1 resulted in an opposite outcome. Moreover, these in vitro findings could be recapitulated in vivo in a xenograft metastasis mouse model. Mechanistically, co-immunoprecipitation combined with mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1), and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to a repression on PIP2 hydrolysis. As a result, the degradation products of PIP2 including DAG and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, cancer metastasis related genes were impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on TAK1 induced phosphorylation of PLCE1 at S1060.