PHOSPHATIDYLINOSITOL 3-KINASE IN MYOGENESIS

Phosphatidylinositol 3-kinase (PI 3-kinase) has been cloned and charac terized in a wide range of organisms. PI 3-kinases are activated by a diversity of extracellular stimuli and are involved in multiple cell p rocesses such as cell proliferation, protein trafficking, cell motilit y, differentiation regulation of cytoskeletal structure, and apoptosis . It has recently been shown that PI 3-kinase is a crucial second mess enger in the signaling of myogenesis. Two structurally unrelated highl y specific inhibitors of PI 3-kinase-wortmannin and LY294002-block the morphological and biochemical differentiation program of different sk eletal-muscle cell models. Moreover, L6E9 myoblasts overexpressing a d ominant-negative mutant of PI 3-kinase p85 regulatory subunit (Delta p 85) are unable to differentiate. Furthermore, PI 3-kinase is specifica lly involved in the insulinlike growth factor (IGF)-dependent myogenic pathway. Indeed the ability of IGF-I, des-1,3-IGF-I, and IGF-II to pr omote cell fusion and muscle-specific protein expression is impaired a fter treatment with PI 3-kinase inhibitors or in cells overexpressing Delta p85. The identification of additional key downstream elements of the IGF/PI 3-kinase myogenic cascade is crucial to a detailed underst anding of the process of muscle differentiation and may generate new t ools for skeletal and cardiac muscle regeneration therapies. (C) 1997, Elsevier Science Inc.