Melanoma inhibitory activity 2 (MIA2) is a novel gene of the MIA gene family. The novel human gene MIA2 encoding a melanoma inhibitory activity (MIA) homologous protein was identified by a GenBank(TM) search. MIA2, together with MIA, belongs to the novel MIA gene family sharing important structural features, significant homology at both the nucleotide and protein levels, and similar genomic organization. MIA2, a protein facilitating protein secretion, is an HNF1A target. The selective expression of MIA2 in hepatocytes is controlled by the hepatocyte nuclear factor (HNF) 1 binding site in the MIA2 promotor. In contrast, in most hepatocellular carcinomas (HCC) MIA2 expression is down-regulated or lost. Full-length hepatic Mia2 structurally and functionally resembled the related Mia3 protein. Mia2 localized to endoplasmic reticulum (ER) exit sites. Mia2's cytosolic C terminus interacted directly with COPII proteins Sec23 and Sec24, whereas its lumenal SH3 domain may facilitate interactions with secretory cargo.