Philip Warren Majerus

His laboratory is interested in defining the mechanisms by which cells respond to extracellular signals both to evoke intracellular repsonses and to modify the extracellular environment with specific reference to cells of blood and blood vessel walls. The laboratory utilizes techniques of biochemistry and molecular biology to study intracellular signaling reactions based on the inositol phosphate signaling pathway. We have defined the pathways and functions involved in the phosphatidylinositol messenger-generating system. The phosphoinositides are minor phospholipids which undergo accelerated breakdown in response to extracellular agonists, such as small molecule effectors, peptide hormones, and growth factors. A host of second messenger molecules are produced, including derivative of arachidonic acid, diacylglyerol, and many inositol phosphates and phospholipids. We have recently discovered several new enzymes and metabolites involved in this pathway and are further exploring these and other new reactions. Enzymes are being isolated and characterized, and their role in the regulation of this complex pathway is under investigation. We have cloned and expressed several of these enzymes. Stable transfectants are being used to define messenger functions. We are exploring how these reactions link to better signaling systems or control cell growth and gene expression. Several of the enzymes of this pathway have recently been shown to be mutated as the cause of human diseases. Mutations in an isozyme of inositol polyphosphate 5-phosphatase cause Lowe syndrome that results in mental retardation, renal tubular acidosis, and eye abnormalities. Inositol polyphosphate 4-phosphatase is required for megakaryocyte differentiation and platelet production.