PI3K: Downstream AKTion Blocks Apoptosis

production of PtdIns-3,4,5-P 3. In vitro, this lipid can be produced by the p170/mCpk-type PI3K that phosphory-Montreal Neurological Institute McGill University lates PtdIns-4-P at the D-3 position (Figure 1) or by a kinase that phosphorylates PtdIns-3-P at the D-4 posi-Montreal, Quebec H3A 2B4 Canada tion (not shown). Thus, the relative levels of PtdIns-3,4-P2 and PtdIns-3,4,5-P3 are independently controlled by † Division of Signal Transduction Beth Israel Deaconess Medical Center a complex set of kinases and phosphatases that have not yet been fully characterized. The importance of this and Department of Cell Biology Harvard Medical School regulation is emphasized by recent evidence that certain SH2 and PH domains interact with PtdIns-3,4,5-P3, but Boston, Massachusetts 02115 not with PtdIns-3,4-P 2 (reviewed by Carpenter and Can-tley, 1996), while the serine/threonine protein kinase Akt/ PKB is activated by PtdIns-3,4-P 2 but not by PtdIns-Extracellular stimuli are transmitted intracellularly by 3,4,5-P 3 (Franke et al., 1997; Klippel et al., 1997). signaling cascades that involve the interaction of macro-Regulation of the Akt/PKB Kinase by PI3K molecules and/or the generation of second messenger Akt/PKB is homologous to the PKA and PKC families molecules that transduce signaling events over a dis-of protein kinases (hence named PKB or Related to A tance between the origin and target of a signal. One and C protein kinase: RAC-PK). It is also the cellular class of such second messenger molecules is generated homolog of the retroviral oncogene v-akt (see references via phosphorylation of phosphoinositides on the D-3 In vivo, the activity of products of PI3K can act on multiple downstream ef-Akt/PKB is regulated by serum and growth factors that fectors that include Src homology-2 (SH2) and Pleckstrin activate PI3K (Burgering and Coffer, 1995; Franke et homology (PH) domains of serine/threonine and tyrosine The role of PI3K in intra-have suggested that PI3K is necessary and sufficient for cellular signaling has been underscored by its implica-growth factor-dependent activation of Akt. First, PDGF tion in a plethora of biological responses. Although it is receptor mutants that are deficient in activating PI3K unlikely that these multiple responses will be explained fail to mediate activation of Akt/PKB (Burgering and by the action of a single downstream target, recent re-Coffer, 1995; Franke et al., 1995). Second, dominant-search from several laboratories indicates that a signal-inhibitory alleles of PI3K prevent activation of Akt (Burg-ing pathway from PI3K to the serine/threonine protein ering and Coffer, 1995), and constitutively activated kinase Akt/PKB …