Growth factors and COX-2/PGE2 enhance lung cancer invasion/metastasis via PI3K/Akt and RAS/Raf. Here, we explored their mechanism of action further. We found first that higher levels of migration inducting gene-7 protein (MIG-7) and PHB phosphorylated at threonine 258 (phospho-PHB T258) are positively correlated with advanced stages of human lung cancer in tissue microarray. PGE2 or growth factors such as EGF, HGF and IGF-1 increased complex formation of phospho-PHB T258 with Ras, phospho-Akt S473, phospho-Raf-1 S338, MEKK1 and IKKα/β S176/180 in the raft domain transiently within 1 hour and MIG-7 in the cytosol 12-24 hours later. Association of phospho-PHB T258 with MEKK1 but not MEKK3 activates IKK/IκB/NF-κB and MEK/ERK to increase cellular COX-2/PGE2 and an E-cadherin suppressor Snail leading to enhancement of epithelial-mesenchymal transition (EMT) and lung cancer migration/invasion. MIG-7, on the other hand, was induced by growth factors and PGE2 via Akt/GSK-3β in a phospho-PHB T258 independent manner. MIG-7 increased two E-cadherin suppressors ZEB-1 and Twist to enhance EMT and cancer migration/invasion. Downregulating phospho-PHB T258 and MIG-7 had an additive effect on attenuating lung cancer invasion/metastasis and prolonging the survival of xenograft mice. Phospho-PHB T258 and MIG-7 may thus play complementary roles in the initiation and sustainment of the effects of growth factors and COX-2/PGE2 on cancer invasion/metastasis.