IL13 signaling through its receptor IL13Ralpha2 plays a critical role in colon cancer invasion and liver metastasis, but the mechanistic features of this process are obscure. In this study, we identified a scaffold protein, FAM120A (C9ORF10), as a signaling partner in this process. FAM120A was overexpressed in human colon cancer cell lines and 55% of human colon cancer specimens. IL13Ralpha2-FAM120A coimmunoprecipitation experiments revealed further signaling network associations that could regulate the activity of IL13Ralpha2, including FAK, SRC, PI3K, G-protein-coupled receptors, and TRAIL receptors. In addition, FAM120A associated with kinesins and motor proteins involved in cargo movement along microtubules. IL13Ralpha2-triggered activation of the FAK and PI3K/AKT/mTOR pathways was mediated by FAM120A, which also recruited PI3K and functioned as a scaffold protein to enable phosphorylation and activation of PI3K by Src family kinases. FAM120A silencing abolished IL13-induced cell migration, invasion, and survival. Finally, antibody blockade of IL13Ralpha2 or FAM120A silencing precluded liver colonization in nude mice or metastasis. In conclusion, we identified FAM120A in the IL13/IL13Ralpha2 signaling pathway as a key mediator of invasion and liver metastasis in colon cancer.