Here, using a combination of molecular, biochemical, bioinformatics, and imaging approaches, we identify a nuclear localization signal (NLS) of GRP78 critical for its nuclear translocation and uncover a transcriptional regulatory mechanism linking nuclear GRP78 to Inhibitor of DNA binding 2 (ID2), a basic helix–loop–helix (bHLH) transcriptional factor which functions as a dominant negative inhibitor of E proteins with tumor suppressor properties in lung cancer (40, 41). Here, ID2 is linked to lung cancer.