Cellular adhesion to the extracellular matrix is essential for morphogenesis, tissue integrity and survival signaling. The best understood adhesion structures are focal adhesions. Inspite of their importance, our knowledge of upstream regulatory factors that integrate focal adhesion assembly with other core cellular processes has remained scarce. To identify potential upstream factors, we have conducted a genome-wide screen for focal adhesion regulators. In this screen depletion of the glycolytic enzyme aldolase A which degrades fructose-1,6-bisphosphate caused an increase in focal adhesion number and cell size. Following up on this finding, we show here that fructose-1,6-bisphosphate is a crucial signaling metabolite transmitting information about the metabolic cell state for the adaptation of cell adhesion and protrusion. At the molecular level, fructose-1,6-bisphosphate relieves RCC2-mediated inhibition of Rac1 by direct binding to RCC2. The increase in Rac1 activity leads to reorganization of the actin cytoskeleton, an increase in focal adhesion assembly and elevated protrusive activity.