Phosphatidate phosphatase (PAP) plays important role in lipid-signaling metabolism in eukaryotic cells. Two distinct types of PAP (PAP1 and PAP2) activity have been distinguished by their subcellular localization and differential sensitivity to N-ethylmaleimide (NEM) and Mg2+. A yeast diacylglycerol pyrophosphate (DGPP) phosphatase (DPP1) and mammalian DGPP phosphatase (PAP2) have been identified as Mg2+-independent and NEM-insensitive membrane-associated. PPAPDC1A (also known as DPPL2) and PPAPDC1B (DPPL1) form a novel type of Mg2+-independent and NEM-sensitive mammalian phosphatidate phosphatase showing broad substrate specificity. Knockdown experiments indicated that this protein is involved with multiple cell signaling pathways, including the JAK-Stat3, MAP kinase, and PKC pathways. PPAPDC1B may also potentiate the estrogen receptor pathway by down-regulating DUSP22.