The PI3K/PKB Signaling Module in Normal and Malignant Hematopoiesis

Hematopoiesis is a complex series of events resulting in the formation of mature blood cells. This process is regulated by cytokines at various levels, including self-renewal, proliferation, and differentiation. Upon binding of cytokines to their cognate receptors, the activity of intracellular signal transduction pathways is regulated, leading to modulation of gene expression. Although our appreciation of the transcriptional regulators of hematopoiesis has developed considerably, until recently, the roles of specific intracellular signal transduction pathways were largely unknown. An important mediator of cytokine signaling implicated in regulation of hematopoiesis is the Phosphatidylinositol-3-Kinase (PI3K) / Protein Kinase B (PKB/c-Akt) signaling module (Figure 1). The PI3K family consists of three distinct subclasses of which, to date, only the class I isoforms have been implicated in regulation of hematopoiesis. Four distinct catalytic class I isoforms have been identified; p110, p110, p110and p110(reviewed by Vanhaesebroeck et al., 2001) These isoforms are predominantly activated by protein tyrosine kinases and form heterodimers with a group a regulatory adapter molecules, including p85, p85, p50 p55, p55and p101(reviewed by Vanhaesebroeck et al., 2001). The most important substrate for these Class I PI3Ks is phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) which can be phosphorylated at the D3 position of the inositol ring upon extracellular stimulation, resulting in the formation of phosphatidylinositol 3,4,5 trisphosphate (PI(3,4,5)P3) (reviewed by Hawkins et al., 2006). PI(3,4,5)P3 subsequently serves as an anchor for pleckstrin homology (PH) domain-containing proteins, such as Protein Kinase B (PKB/ c-akt) (Burgering & Coffer, 1995). Activation of PKB requires phosphorylation on both Thr308, in the activation loop, by phosphoinositide-dependent kinase 1 (PDK1) and Ser473, within the carboxyl-terminal hydrophobic motif, by the MTORC2 complex that consists of multiple proteins, including Mammalian Target of Rapamycin (mTOR) and Rictor (Sarbassov et al., 2005). PKB itself subsequently regulates the activity of multiple downstream effectors, including the serine/threonine kinase Glycogen Synthase Kinase-3 (GSK-3) (Cross et al., 1995), members of the FoxO subfamily of forkhead transcription factors FoxO1, FoxO3, and FoxO4 (Brunet et al., 1999; Kops et al., 1999) and the serine/threonine kinase mammalian target of rapamycin (mTOR) as part of the MTORC1 complex, which also includes the regulatory