Updated project metadata. Cancer metastasis is a complex mechanism involving multiple processes. In an earlier study, we reported that the levels of serine/threonine phosphatase POPX2 were positively correlated with cancer cell motility through modulating MAPK signaling. Surprisingly, here we found that POPX2 knockdown cells induced more numerous and larger tumor nodules in lungs in longer term animal studies, suggesting that lower levels of POPX2 may favor tumor progression in later stages of metastasis. We hypothesize that POPX2 may do so by modulation of angiogenesis. Secretome analysis of POPX2-knockdown MDA-MB-231 cells using SILAC-mass spectrometry and cytokine array showed that silencing of POPX2 leads to increased secretion of exosomes, which may in turn induce multiple pro-angiogenic cytokines. This study, combined with our earlier findings, suggests that a single ubiquitously expressed phosphatase POPX2 influences cancer metastasis via modulating multiple biological processes including MAPK signaling and exosome-cytokine secretion.