PI3Kβ - a versatile transducer for GPCR, RTK and small GTPase signaling.

The phosphoinositide 3-kinase (PI3K) family includes 8 distinct catalytic subunits and seven regulatory subunits. Only two PI3Ks are directly regulated downstream from G Protein-Coupled Receptors (GPCRs): the Class I enzymes PI3Kβ and PI3Kγ. Both enzymes produce phosphatidylinositol (3,4,5)P3in vivo, and are regulated by both heterotrimeric G-proteins and small GTPases from the Ras or Rho families. However, PI3Kβ is also regulated by direct interactions with receptor tyrosine kinases (RTKs) and their tyrosine phosphorylated substrates, and like the Class II and III PI3Ks, it binds activated Rab5. The unusually complex regulation of PI3Kβ by small and trimeric G-proteins and RTKs leads to a rich landscape of signaling responses at the cellular and organismic level. This review will focus first on the regulation of PI3Kβ activity in vitro and in cells, and will summarize the biology of PI3Kβ signaling in distinct tissues and in human disease.