PTEN protein phosphatase activity regulates metastasis by targeting PKCδ

<i>PTEN</i> acts as a tumor suppressor through its lipid and protein phosphatase activities. We previously reported that PTEN phosphatase inhibits metastasis independent of its lipid phosphatase. To determine PTEN phosphatase downstream substrates and their role precisely in metastatic suppression, we used proteomic approaches to identify PKCδ as PTEN protein phosphatase substrates. We show that the inactivation of PTEN protein phosphatase activity causes loss of the capability to dephosphorylate PKCδ at S643, T505, and Y311, but wild-type or PTEN lipid phosphatase deficient mutants can maintain. We then established knock-in and knock-out models to confirm that PTEN protein phosphatase is required to inhibit PKCδ phosphorylation and necessary to suppress tumor metastasis. Notably, we found that PKCδ could promote metastasis of melanoma cells with wild-type PTEN. Still, the knockdown of PKCδ abrogated the metastatic potential of PTEN phosphatase-deficient melanoma cells, linking PTEN metastasis suppressor function to PTEN protein phosphatase and its substrate PKCδ.