Pleiotropic effects of moonlighting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in cancer progression, invasiveness, and metastases.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) may represent the quintessential example of a moonlighting protein. The latter are a new, intriguing class of cell proteins which exhibit multiple activities in different subcellular locales apart from their initially, well-characterized function. As such, apart from its classical role in energy production, membrane-bound GAPDH is required for membrane fusion, endocytosis and, intriguingly, for iron transport. Cytoplasmic GAPDH regulates mRNA stability and is required for ER to Golgi trafficking. Nuclear GAPDH is involved in apoptosis, transcriptional gene regulation, the maintenance of DNA integrity, as well as nuclear tRNA export. Paradoxically, the etiology of a number of human pathologies is dependent upon GAPDH structure and function. In particular, recent evidence indicates a significant role for moonlighting GAPDH in tumorigenesis. Specifically, these include its role in the survival of tumor cells, in tumor angiogenesis, as well as its control of tumor cell gene expression and posttranscriptional regulation of tumor cell mRNA. Each of these activities correlates with increased tumor progression and, unfortunately, a poor prognosis for the afflicted individual.