Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate (By similarity). Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production (PubMed:23726973). Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death (PubMed:23726973). Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity (By similarity). In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3 (PubMed:22044588). Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage (PubMed:22044588). Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation (PubMed:23726973). Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions (PubMed:24872551). Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner. Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses (By similarity). Involved in intestinal tumor progression (PubMed:23726973). beta-D-fructose 2,6-bisphosphate + H2O = beta-D-fructose 6-phosphate + phosphate Interacts with HK2; the interaction increases hexokinase HK2 activity in a hypoxia- and HIF1A-dependent manner, resulting in the regulation of mitochondrial membrane potential, thus increasing NADPH production and decreasing intracellular ROS levels. Translocated to the mitochondria during hypoxia in a HIF1A-dependent manner. Colocalizes with HK2 in the mitochondria during hypoxia. Translocated to the nucleus during hypoxia and/or genome stress-induced DNA damage responses in cancer cells (By similarity). Translocation to the mitochondria is enhanced in ischemic cortex after reperfusion and/or during oxygen and glucose deprivation (OGD)/reoxygenation insult in primary neurons (PubMed:24872551). Expressed in olfactory bulb, cerebellum, and cortex (PubMed:24872551). Expressed in neurons and astrocytes (PubMed:24872551) (at protein level). Expressed in intestinal crypt (PubMed:23726973). Up-regulated by hypoxia in cardiac myocytes in a p53/TP53-dependent manner (PubMed:20935145). Up-regulated in ischemic cortex after reperfusion in a p53/TP5-independent manner (PubMed:24872551). Up-regulated in primary neurons by oxygen and glucose deprivation (OGD)/reoxygenation insult in a p53/TP5-independent manner (at protein level) (PubMed:24872551). Up-regulated in ischemic myocardium in a p53/TP5-dependent manner (PubMed:22044588). Up-regulated in small intestine after gamma irradiation damage (PubMed:23726973). Mice are viable and fertile and show no obvious developmental defects (PubMed:23726973). Following intestine ablation by gamma irradiation, adult mice display a reduction in the size and number of proliferating intestinal crypts and an increase in cell death (PubMed:23726973). Mice display reduced intestinal tumor progression compared to wild-type mice (PubMed:23726973). In response to ischemic myocardium injury, display an increase in the ability to stimulate myocyte mitophagy in ischemic border zones through a ROS-induced and BNIP3 activation dependent manner leading to a reduction of defective mitochondria and myocyte cell death, and hence a better recovery of cardiac function (PubMed:22044588). Belongs to the phosphoglycerate mutase family. Not expected to have any kinase activity.