We report here that the E7 oncoprotein encoded by the oncogenic human papillomavirus (HPV) type 16 binds to the glycolytic enzyme type M 2 pyruvate kinase (M2-PK). M2-PK occurs in a tetrameric form with a high affinity to its substrate phosphoenolpyruvate and a dimeric form with a low affinity to phosphoenolpyruvate, and the transition between both conformations regulates the glycolytic f lux in tumor cells. The glycolytic intermediate fructose 1,6-bisphosphate induces the reassociation of the dimeric to the tetrameric form of M2-PK. The expression of E7 in an experimental cell line shifts the equilibrium to the dimeric state despite a significant increase in the fructose 1,6-bisphosphate levels. Investigations of HPV-16 E7 mutants and the nononcogenic HPV-11 subtype suggest that the interaction of HPV-16 E7 with M2-PK may be linked to the transforming potential of the viral oncoprotein.Unicellular organisms have a variety of sensing mechanisms to adapt the cell proliferation rate to variations in their environmental nutrient supply. Several gene products, like the ras or cdc kinase proteins, which are involved in nutrient sensing in yeast (1, 2), are conserved during the evolution of multicellular organisms, and in mammals, these gene products often are altered in tumors. Despite our knowledge about the protein machinery regulating cell proliferation increasing tremendously over the recent years, we are still at the beginning to understand how nutrients contribute to proliferation control in multicellular organisms. There is, however, quite good evidence that phosphometabolites derived from both glycolysis (for recent review, see ref.3) and the pentose phosphate pathway (ref. 4 and references therein) provide some of the signals linking metabolic conditions to cell proliferation. The glycolytic phosphometabolites, which are necessary for the biosynthesis of nucleic acids, phospholipids, and complex carbohydrates, are up-regulated in the G 1 phase of the cell cycle (for recent review, see