Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC 3800, AUSTRALIA.
Phosphoinositides are membrane bound signalling molecules that interact with a plethora of effector proteins to regulate vesicular trafficking, metabolism, actin dynamics, cell proliferation and survival. The generation and turnover of specific phosphoinositide species is achieved by the activity of both phosphoinositide kinases and phosphatases, which phosphorylate and dephosphorylate respectively phosphates from the inositol head group of phosphoinositide signalling molecules. Phosphoinositide 3-kinase (PI3K) generates the signalling molecule PI(3,4,5)P3 which can be dephosphorylated by the inositol polyphosphate 5-phosphatases to generate PI(3,4)P2 which is in turn dephosphorylated at the plasma membrane and on early endosomes by 4-phosphatases to generate PI(3)P. Both PI(3,4,5)P3 and PI(3,4)P2 are required for the activation of the serine threonine kinase Akt, which in turn activates a plethora of down-stream signalling cascades that promote cell survival, proliferation, migration, angiogenesis and metabolism. There are ten mammalian 5-phosphatases and recently several of these enzymes have been implicated in embryonic development. Genetic mutations in the 5-phosphatase, INPP5E, are causative of the ciliopathy syndromes of Joubert and MORM, which are associated with mental retardation, abnormal neuronal development, polydactyly and other abnormalities. Deletion of murine Inpp5e causes mid-gestation lethality with ciliopathy phenotypes including neural tube defects, exencephaly, polydactyly and polycystic kidneys providing an ideal model to examine its role in ciliopathies. The molecular mechanisms by which 5-phosphatases by degrading membrane bound phosphoinositide signalling molecules in turn regulate embryonic and post-natal development of specific tissues will be explored.