Understanding the role of AKT-independent signaling downstream of PI3K is certainly important because: a) AKT isn’t always hyperactivated in the context of mutations in PI3K pathway components such as for example and that raise PIP3 amounts in cancer; b) many important cellular procedures are motivated by PI3K-dependent but AKT-independent signaling to market malignant phenotypes, and; c) systems of level of resistance to PI3K pathway inhibitors can involve the activation of PI3K-dependent signaling protein that can replacement for AKT signaling

Understanding the role of AKT-independent signaling downstream of PI3K is certainly important because: a) AKT isn’t always hyperactivated in the context of mutations in PI3K pathway components such as for example and that raise PIP3 amounts in cancer; b) many important cellular procedures are motivated by PI3K-dependent but AKT-independent signaling to market malignant phenotypes, and; c) systems of level of resistance to PI3K pathway inhibitors can involve the activation of PI3K-dependent signaling protein that can replacement for AKT signaling. malignancy and represents a recently available example of a highly effective healing target in cancers. These systems how understanding PI3K-dependent high light, but AKT-independent, signaling systems that drive cancer progression will be crucial for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer. Introduction Phosphoinositide 3-kinase (PI3K) signaling plays a central role in cellular physiology, coordinating insulin signaling during organismal growth and mediating critical cellular processes such as glucose homeostasis, protein synthesis, cell proliferation, and survival. This pathway has been an intense area of investigation, particularly in light of cancer genetics studies that have revealed it to be one of the Levomefolic acid most frequently altered pathways in human malignancies that controls most hallmarks of cancer, including cell proliferation, survival, genomic instability, and metabolism [1]. Consequently, PI3K signaling has emerged as an attractive target for cancer therapy, and many drugs that inhibit various pathway components are currently in clinical trials [2, 3]. Class I PI3K transduces upstream signals from receptor tyrosine kinases (RTKs) and PLAUR G protein-coupled receptors (GPCRs) by phosphorylating the 3-hydroxyl group of the inositol ring of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) [4, 5]. PIP3 serves as a critical lipid second messenger that recruits cytosolic proteins containing pleckstrin homology (PH) domains to the plasma membrane to promote either their activation or co-localization with other effector proteins [6C8]. It should be noted that only a small subset of PH domains in the human genome are thought to bind PIP3 with high affinity and specificity (10C20% out of ~290 PH domains have been shown to robustly bind phosphoinositides, with some of these robustly binding PI-3,4-P2 or PI-4,5-P2 but not PIP3) [9, 10]. Of the PH domain-containing proteins that do bind PIP3, the serine/threonine AGC-family protein kinase AKT has received the greatest attention, especially for its multi-faceted roles in promoting glucose metabolism and cancer [11, 12]. However, recent advances have demonstrated critical mechanisms by which other proteins with PIP3-binding PH domains contribute to cancer progression. Understanding the role of AKT-independent signaling downstream of PI3K is important because: a) AKT is not always hyperactivated in the context of mutations in PI3K pathway components such as and that elevate PIP3 levels in cancer; b) many critical cellular processes are driven by PI3K-dependent but AKT-independent signaling to promote malignant phenotypes, and; c) mechanisms of resistance to PI3K pathway inhibitors can involve the activation of PI3K-dependent signaling proteins that can substitute for AKT signaling. To illustrate this, in this review we highlight three AKT-independent signaling branches downstream of PI3K that have recently been shown to have critical roles in promoting cancer progression: the PDK1-mTORC2-SGK axis, Rac signaling, and the TEC family kinases. Substituting for AKT signaling: The PDK1-mTORC2-SGK axis PDK1 (3-phosphoinositide-dependent protein kinase 1) and the multi-protein complex mTORC2 (mechanistic target of rapamycin complex 2) are PI3K-dependent, PH domain-containing kinases that coordinately activate several growth factor-sensitive AGC kinases, including AKT (also known as protein kinase B), SGKs (serum and glucocorticoid-regulated kinase), and certain PKCs (protein kinase C), by phosphorylating their activation loops and hydrophobic motifs (HM), respectively [13]. PDK1 is a constitutively active kinase with two major regulatory domains: a C-terminal PH domain that binds PIP3, and.Therefore, developing inhibitors of Rac (Table 1) and exploring their potential as therapeutic options for cancer treatment is an active area of investigation [65]. Activation of non-receptor tyrosine kinase signaling: TEC family kinases Of the 90 tyrosine kinases in the human genome, 58 are membrane-spanning receptor tyrosine kinases (RTKs), while the remaining 32 lack transmembrane domains and are classified as nonreceptor tyrosine kinases (NRTKs). family kinase BTK has a critical role in B cell function and malignancy and represents a recent example of an effective therapeutic target in cancer. These mechanisms highlight how understanding PI3K-dependent, but AKT-independent, signaling mechanisms that drive cancer progression will be crucial for the development of novel and Levomefolic acid more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer. Introduction Phosphoinositide 3-kinase (PI3K) signaling plays a central role in cellular physiology, coordinating insulin signaling during organismal growth and mediating critical cellular processes such as glucose homeostasis, protein synthesis, cell proliferation, and survival. This pathway has been an intense area of investigation, particularly in light of cancer genetics studies that have revealed it to be one of the most frequently altered pathways in human malignancies that controls most hallmarks of cancer, including cell proliferation, survival, genomic instability, and metabolism [1]. Consequently, PI3K signaling has emerged as an attractive target for cancer therapy, and many drugs that inhibit various pathway components are currently in clinical trials [2, 3]. Class I PI3K transduces upstream signals from receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) by phosphorylating the 3-hydroxyl group of the inositol ring of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) [4, 5]. PIP3 serves as a critical lipid second messenger that recruits cytosolic proteins containing pleckstrin homology (PH) domains to the plasma membrane to promote either their activation or co-localization with other effector proteins [6C8]. It should be noted that only a small subset of PH domains in the human genome are thought to bind PIP3 with high affinity and specificity (10C20% out of ~290 PH domains have been shown to robustly bind phosphoinositides, with some of these robustly binding PI-3,4-P2 or PI-4,5-P2 but not PIP3) [9, 10]. Of the PH domain-containing proteins that do bind PIP3, the serine/threonine AGC-family protein kinase AKT has received the greatest attention, especially for its multi-faceted roles in promoting glucose metabolism and cancer [11, 12]. However, recent advances have demonstrated critical mechanisms by which other proteins with PIP3-binding PH domains contribute to cancer progression. Understanding the role of AKT-independent signaling downstream of PI3K is important because: a) AKT is not always hyperactivated in the context of mutations in PI3K pathway components such as and that elevate PIP3 levels in cancer; b) many critical cellular processes are driven by PI3K-dependent but AKT-independent signaling to promote malignant phenotypes, and; c) mechanisms of resistance to PI3K pathway inhibitors can involve the activation of PI3K-dependent signaling proteins that can substitute for AKT signaling. To illustrate this, in this review we highlight three AKT-independent signaling branches downstream of PI3K that have recently been shown to have critical roles in promoting cancer progression: the PDK1-mTORC2-SGK axis, Rac signaling, and the TEC family kinases. Substituting for AKT signaling: The PDK1-mTORC2-SGK axis PDK1 (3-phosphoinositide-dependent protein kinase 1) and the multi-protein complex mTORC2 (mechanistic target of rapamycin complex 2) are PI3K-dependent, PH domain-containing kinases that coordinately activate several growth factor-sensitive AGC kinases, including AKT (also known as protein kinase B), SGKs (serum and glucocorticoid-regulated kinase), and certain PKCs (protein kinase C), by phosphorylating their activation loops and hydrophobic motifs (HM), respectively [13]. PDK1 is a constitutively active kinase with two major regulatory domains: a C-terminal PH domain that binds PIP3, and a PIF-binding pocket within its catalytic domain that docks on the phosphorylated HM of AGC kinases, a region also Levomefolic acid known as the PDK1-interacting fragment (PIF) [14C17]. The PH domain allows PDK1 to co-localize with AKT at the plasma membrane and phosphorylate its activation loop upon PI3K activation. SGKs and PKCs, however, lack PH domains, and the PDK1 PH domain is not required for their phosphorylation; rather, PDK1 docks on the phosphorylated HM of these kinases through its PIF-binding pocket in order to phosphorylate their activation loops (atypical.