The multicellular behavior of the myxobacterium Myxococcus xanthus requires the participation of an elevated number of signal-transduction mechanisms to coordinate the cell movements and the sequential changes in gene expression patterns that lead to the morphogenetic and differentiation events. These signaltransduction mechanisms are mainly based on two-component systems and on the reversible phosphorylation of protein targets mediated by eukaryotic-like protein kinases and phosphatases. Among all these factors, protein phosphatases are the elements that remain less characterized. Hence, we have studied in this work the physiological role and biochemical activity of the protein phosphatase of the family PPP (phosphoprotein phosphatases) designated as Pph2, which is forming part of the same operon as the two-component system phoPR1. We have demonstrated that this operon is induced upon starvation in response to the depletion of the cell energy levels. The increase in the expression of the operon contributes to an efficient use of the scarce energy resources available for developing cells to ensure the completion of the life cycle. In fact, a ⌬pph2 mutant is defective in aggregation, sporulation yield, morphology of the myxospores, and germination efficiency. The yeast two-hybrid technology has shown that Pph2 interacts with the gene products of MXAN_1875 and 5630, which encode a hypothetical protein and a glutamine synthetase, respectively. Because Pph2 exhibits Ser/Thr, and to some extent Tyr, Mn 2؉ -dependent protein phosphatase activity, it is expected that this function is accomplished by dephosphorylation of the specific protein substrates.Myxococcus xanthus is a soil-dwelling ␦-Proteobacterium that undergoes a life cycle unique among the prokaryotes. During growth, cells form predatory communities known as swarms, which feed cooperatively. Upon starvation, cells initiate a multicellular developmental program that culminates with the formation of macroscopic fruiting bodies filled with resistant myxospores. The spores remain dormant until nutrients are available again, when they germinate and initiate a new vegetative cycle (1). This complex lifestyle forces the cells not only to scrutinize all the changes in their environment, but also to maintain a precise communication with each other to coordinate their movement and behavior. In fact, signal-transduction mechanisms of diverse nature have been reported to function in the cell synchronization required during development (2, 3). One of these mechanisms is based on eukaryotic-like protein kinases (ELKs), 3 which originate phosphoesters on Ser/ Thr/Tyr residues. Thus, the myxobacterial kinome is the largest one among the prokaryotes, which seems to correlate with their multicellular behavior (4). The presence of ELKs implies the need of protein phosphatases (PPs) to revert the action of the kinases. These two types of proteins will function together to switch on and off the signal-transduction pathways where they participate by their opposite action on speci...