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Akt pathway: From signaling to diseases”
Advances in Biological Regulation xxx (2015) 1e3
Contents lists available at ScienceDirect
Advances in Biological Regulation journal homepage: www.elsevier.com/locate/jbior
Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”
This special issue of Advance in Biological Regulation focuses on the phosphoinositide 3-kinase (PI3-kinase)/Akt pathway, its evolutionary distribution and its implication in human pathologies particularly in pancreatic cancer and cardiovascular diseases. The development of appropriate therapeutic approaches targeting this signaling pathway in those pathologies will be discussed. In their contributions the authors clearly show how this field is continuously evolving from cell signaling researches to a domain of broad medical significance and impact. They also show how data obtained with pharmacological inhibitors in preclinical and clinical studies increase our knowledge of molecular mechanisms and of their implication in pathophysiology. Since their initial discovery as a lipid kinase activity associated with a viral oncoprotein, and then with growth factor receptors, class I PI3-kinases have been demonstrated as major components of the intracellular signal transduction machinery. There are four isoforms of Class I PI3-kinases (p110a,b,d,g), two of them are ubiquitously expressed (a,b) while the others have a much more restricted tissue distribution (d,g are mainly expressed in hematopoietic tissues). Class I PI3kinase isoforms, composed of a catalytic subunit of 110 kDa and a regulatory subunit, transduce signals from various cell stimuli acting through receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors or G-protein-coupled receptors. Following cell stimulation these kinases generate the lipid second messenger phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3) to orchestrate the localization and activation of intracellular protein effectors involved in many aspects of cell function. Indeed, the rapid production of PtdIns(3,4,5)P3 pools serve as plasma membrane docking sites for proteins that harbor pleckstrin-homology (PH) domains allowing the spatiotemporal formation of highly efficient signal transfer particles. Thirty to fifty mammalian proteins with PH domain are thought to be regulated by Class I PI3-kinases, contributing to the wide input of this pathway in cell regulations. One of the best characterized downstream effector is the serine/threonine kinase Akt and its upstream activator called phosphoinositide-dependent kinase 1 (PDK1). Akt is a protooncogene (the mammalian homologue of the retroviral transforming protein v-Akt) which PH domain interacts with PtdIns(3,4,5)P3 thereby promoting its phosphorylation on Thr308 by PDK1. Additional phosphorylation on Ser473 by mammalian target of rapamycin complex 2 (mTORC2) is critical for full Akt activation. Other kinases such as DNA-PK may phosphorylate this site in certain conditions. Once phosphorylated on these aminoacid residues, Akt has pleiotropic roles including regulation of metabolism, growth, proliferation, survival, transcription and protein synthesis. This plethora of effects are mediated by the numerous intracellular substrates of Akt. The three highly related isoforms of Akt (Akt1, Akt2 and Akt3) share many substrates but have also some isoform-specific substrates. They phosphorylate proteins containing the consensus phosphorylation motif RxRxxS/T. Akt regulates cell growth and proliferation through its effects on PRAS40 and tuberous sclerosis protein 2 (TSC2) and the downstream mTORC1 signaling, and via phosphorylation of the cyclindependant kinases (CDK) inhibitors p21 and p27. Akt also controls cell survival through inhibition of pro-apoptotic proteins or signals. Akt has an important input in the regulation of metabolism through the control of AS160, a member the GTPase-activating protein for Rabs (RabGAP) family which regulates GLUT4 trafficking, and through the activation of PFKFB2. In addition, Akt has been shown to regulate proteins involved in neuronal functions, NF-kB signaling and cell migration and invasion. The PI3-kinase/Akt pathway is tightly regulated and several important negative regulators of the pathway have been identified, including the protein phosphatase 2 (PP2A), the PH-domain leucine-rich-repeat-containing protein phosphatases (PHLPP1/2) and the lipid phosphatase and tensin homolog (PTEN). Akt can be dephosphorylated by PP2A (at T308) and by PHLPP1/2 (at S473), while the tumor suppressor PTEN is known to dephosphorylate PtdIns(3,4,5)P3 at the position 3 of the inositol ring thereby down regulating Akt recruitment and activity. Dysregulation of the PI3-kinase/Akt pathway is implicated in several human diseases. Aberrant activation of the PI3kinase/Akt pathway has been widely implicated in many types of cancer. Several oncogenes activate this pathway, including Ras which can directly impact on Class IA PI3-kinase isoforms activity by binding to their catalytic subunits. http://dx.doi.org/10.1016/j.jbior.2015.07.001 2212-4926/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Payrastre, B., Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”, Advances in Biological Regulation (2015), http://dx.doi.org/10.1016/j.jbior.2015.07.001
2
B. Payrastre, L. Cocco / Advances in Biological Regulation xxx (2015) 1e3
Moreover, two frequent gain of function mutations in the PIK3CA gene, encoding the catalytic subunit of PI3-kinase a (mutations E545K and H1047R in p110a), are observed in solid tumors. In addition, PTEN is frequently mutated or lost in human tumors resulting in decreased PtdIns(3,4,5)P3 hydrolysis and increased or sustained downstream signaling. Some gain of function mutations in Akt have also been described. Thus, the PI3-kinase/Akt signaling is one of the most commonly deregulated signaling pathways in cancer and has emerged as a very attractive target for cancer therapy. Pharmaceutical companies have focused much attention on these signaling molecules over the ten past years and several class I PI3-kinases inhibitors, either highly specific of one of the four isoforms or targeting several members of the family, have entered clinical trials. Importantly, one of these molecules, the specific PI3-kinase d inhibitor idelalisib, has been recently approved by the “Food and Drug Administration” in the US for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. In solid cancer, targeting selectively one isoform of PI3-kinase may not be sufficient but association with other drugs used in chemotherapy or targeting specific proteins such as Poly (ADP-ribose) polymerase (PARP) could yield therapeutic benefits. Besides cancer, the PI3-kinase/Akt pathway also plays important roles in cardiovascular diseases. In 2012, cardiovascular diseases were responsible of 31% of all global deaths worldwide and more than 23 million people will die annually from these diseases by 2030. Among cardiovascular diseases, atherosclerosis and its thrombotic complications, including ischaemic heart disease and stroke, are major causes of mortality and new therapeutic options to treat these pathologies would be welcome. The mechanisms involved in the development of these diseases implicate a variety of signaling pathways and cell types, including endothelial cells, smooth muscle cells and platelets. Experimental models of cardiovascular diseases in genetically modified animals have provided proof-of-concept that class I PI3-kinase blockade can modify disease development and progression. Therapeutic inhibition of class I PI3-kinase isoforms constitutes promising strategies to restrain the development of atherosclerosis, prevent restenosis after angioplasty and stenting and blunt platelet aggregation to reduce arterial thrombotic risk. In this special issue of Advance in Biological Regulation, researchers from five teams working either in the field of pancreatic cancer or on cardiovascular diseases have critically discussed the implication of class I PI3-kinases signaling in these pathologies and its potential therapeutic targeting. Kriplani, Leslie and colleague have summarize our current knowledge of the class I PI3-kinase pathway components including kinases, downstream effectors of PtdIns(3,4,5)P3 and regulatory phosphatases. They also explored the evolutionary distribution of class I PI3-kinase pathway components and related this knowledge with their function. The apparent evolutionary conservation of many key actors of the PI3-kinase pathway likely reflects conserved functions from flies to mammals but also specialized roles in specific organisms and cells. Reconstruction of the evolutionary relationships among components of this pathway brings interesting information related to their roles in diseases and their potential status of drug targets. The implication of the PI3-kinase/Akt pathway in pancreatic cancer is discussed extensively in the reviews by Fitzgerald, McCubrey and colleagues and by Baer, Guilhermet and colleagues. Pancreatic cancer is a relatively common cancer which incidence is increasing. It is one of the most lethal cancers, with a 5-year death rate of 95% of diagnosed patients highlighting how new treatment options are urgently needed. Fitzgerald, McCubrey and colleagues discussed the role of the PI3-kinase/ Akt signaling pathway downstream of EGFR and KRAS in pancreatic cancer and in pancreatic cancer stem cells. Their detailed analysis focuses on recent advances in the complex and interconnected signaling circuitries found in these cancer cells and their therapeutic implications. In the review by Baer, Guilhermet and colleagues, the role of the different isoforms of PI3-kinase in oncogenesis is critically discussed as well as their importance in pancreatic ductal adenocarcinoma. The authors describe how the PI3kinase pathway plays a role both in the cancer cell but also in the tumor microenvironment. They also discuss about the therapeutic potential of targeting Class I PI3-kinase isoforms for pancreatic cancer treatment and the relevance of a strategy using isoform-specific inhibitors of PI3-kinases versus pan-PI3K inhibitors, considering potential adverse effects. In their review, Lupieri, Laffargue and colleagues discuss in detail the role of the different class I PI3-kinases in arterial diseases such as atherosclerosis and in restenosis after angioplasty. They describe their respective implication in endothelial cells, smooth muscle cells but also in the immune cells and highlight the highly-intertwined interactions between these cells in the development arterial wall diseases. This review also summarizes the rationale of PI3-kinase isoforms inhibition in the most prevalent cardiovascular diseases, and the available data on the therapeutic effects of PI3K inhibitors in preclinical models. Guidetti, Canobbio and Torti extensively discussed the implication of the different class I PI3K in blood platelet activation and more particularly their role in integrin signaling and in arterial thrombosis. Blood platelets are imperative to promptly arrest bleeding following vascular injury but upon rupture of an unstable atherosclerotic plaque, they form an occlusive thrombus (called atherothrombosis) preventing oxygen supply to brain or heart, which results in myocardial infarction or stroke. Patients with high risk for arterial thrombosis are treated with antiplatelet medications such as aspirin and clopidogrel. Although the current anti-platelet treatments do reduce the mortality and morbidity in different groups of patients, these treatments increase the bleeding risk. Therefore novel, improved anti-platelet therapies are needed. The authors of this review discuss the relevance of targeting class I PI3-kinase isoforms for future therapy to prevent arterial thrombosis without increasing the bleeding risk.
Please cite this article in press as: Payrastre, B., Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”, Advances in Biological Regulation (2015), http://dx.doi.org/10.1016/j.jbior.2015.07.001
B. Payrastre, L. Cocco / Advances in Biological Regulation xxx (2015) 1e3
3
Bernard Payrastre * INSERM UMR 1048, Institut des Maladies M etaboliques et Cardiovasculaires (I2MC), Universit e Toulouse III Paul Sabatier and Centre Hospitalier Universitaire de Toulouse, Laboratoire d'H ematologie, 1, Avenue Jean Poulh es BP 84225, 31432 Toulouse Cedex 4, France Lucio Cocco Cellular Signalling Laboratory, Department of Biomedical Sciences, University of Bologna, Via Irnerio, 48, I-40126 Bologna, Italy Corresponding author. E-mail address: [email protected] Available online xxx
Please cite this article in press as: Payrastre, B., Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”, Advances in Biological Regulation (2015), http://dx.doi.org/10.1016/j.jbior.2015.07.001
Contents lists available at ScienceDirect
Advances in Biological Regulation journal homepage: www.elsevier.com/locate/jbior
Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”
This special issue of Advance in Biological Regulation focuses on the phosphoinositide 3-kinase (PI3-kinase)/Akt pathway, its evolutionary distribution and its implication in human pathologies particularly in pancreatic cancer and cardiovascular diseases. The development of appropriate therapeutic approaches targeting this signaling pathway in those pathologies will be discussed. In their contributions the authors clearly show how this field is continuously evolving from cell signaling researches to a domain of broad medical significance and impact. They also show how data obtained with pharmacological inhibitors in preclinical and clinical studies increase our knowledge of molecular mechanisms and of their implication in pathophysiology. Since their initial discovery as a lipid kinase activity associated with a viral oncoprotein, and then with growth factor receptors, class I PI3-kinases have been demonstrated as major components of the intracellular signal transduction machinery. There are four isoforms of Class I PI3-kinases (p110a,b,d,g), two of them are ubiquitously expressed (a,b) while the others have a much more restricted tissue distribution (d,g are mainly expressed in hematopoietic tissues). Class I PI3kinase isoforms, composed of a catalytic subunit of 110 kDa and a regulatory subunit, transduce signals from various cell stimuli acting through receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors or G-protein-coupled receptors. Following cell stimulation these kinases generate the lipid second messenger phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3) to orchestrate the localization and activation of intracellular protein effectors involved in many aspects of cell function. Indeed, the rapid production of PtdIns(3,4,5)P3 pools serve as plasma membrane docking sites for proteins that harbor pleckstrin-homology (PH) domains allowing the spatiotemporal formation of highly efficient signal transfer particles. Thirty to fifty mammalian proteins with PH domain are thought to be regulated by Class I PI3-kinases, contributing to the wide input of this pathway in cell regulations. One of the best characterized downstream effector is the serine/threonine kinase Akt and its upstream activator called phosphoinositide-dependent kinase 1 (PDK1). Akt is a protooncogene (the mammalian homologue of the retroviral transforming protein v-Akt) which PH domain interacts with PtdIns(3,4,5)P3 thereby promoting its phosphorylation on Thr308 by PDK1. Additional phosphorylation on Ser473 by mammalian target of rapamycin complex 2 (mTORC2) is critical for full Akt activation. Other kinases such as DNA-PK may phosphorylate this site in certain conditions. Once phosphorylated on these aminoacid residues, Akt has pleiotropic roles including regulation of metabolism, growth, proliferation, survival, transcription and protein synthesis. This plethora of effects are mediated by the numerous intracellular substrates of Akt. The three highly related isoforms of Akt (Akt1, Akt2 and Akt3) share many substrates but have also some isoform-specific substrates. They phosphorylate proteins containing the consensus phosphorylation motif RxRxxS/T. Akt regulates cell growth and proliferation through its effects on PRAS40 and tuberous sclerosis protein 2 (TSC2) and the downstream mTORC1 signaling, and via phosphorylation of the cyclindependant kinases (CDK) inhibitors p21 and p27. Akt also controls cell survival through inhibition of pro-apoptotic proteins or signals. Akt has an important input in the regulation of metabolism through the control of AS160, a member the GTPase-activating protein for Rabs (RabGAP) family which regulates GLUT4 trafficking, and through the activation of PFKFB2. In addition, Akt has been shown to regulate proteins involved in neuronal functions, NF-kB signaling and cell migration and invasion. The PI3-kinase/Akt pathway is tightly regulated and several important negative regulators of the pathway have been identified, including the protein phosphatase 2 (PP2A), the PH-domain leucine-rich-repeat-containing protein phosphatases (PHLPP1/2) and the lipid phosphatase and tensin homolog (PTEN). Akt can be dephosphorylated by PP2A (at T308) and by PHLPP1/2 (at S473), while the tumor suppressor PTEN is known to dephosphorylate PtdIns(3,4,5)P3 at the position 3 of the inositol ring thereby down regulating Akt recruitment and activity. Dysregulation of the PI3-kinase/Akt pathway is implicated in several human diseases. Aberrant activation of the PI3kinase/Akt pathway has been widely implicated in many types of cancer. Several oncogenes activate this pathway, including Ras which can directly impact on Class IA PI3-kinase isoforms activity by binding to their catalytic subunits. http://dx.doi.org/10.1016/j.jbior.2015.07.001 2212-4926/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Payrastre, B., Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”, Advances in Biological Regulation (2015), http://dx.doi.org/10.1016/j.jbior.2015.07.001
2
B. Payrastre, L. Cocco / Advances in Biological Regulation xxx (2015) 1e3
Moreover, two frequent gain of function mutations in the PIK3CA gene, encoding the catalytic subunit of PI3-kinase a (mutations E545K and H1047R in p110a), are observed in solid tumors. In addition, PTEN is frequently mutated or lost in human tumors resulting in decreased PtdIns(3,4,5)P3 hydrolysis and increased or sustained downstream signaling. Some gain of function mutations in Akt have also been described. Thus, the PI3-kinase/Akt signaling is one of the most commonly deregulated signaling pathways in cancer and has emerged as a very attractive target for cancer therapy. Pharmaceutical companies have focused much attention on these signaling molecules over the ten past years and several class I PI3-kinases inhibitors, either highly specific of one of the four isoforms or targeting several members of the family, have entered clinical trials. Importantly, one of these molecules, the specific PI3-kinase d inhibitor idelalisib, has been recently approved by the “Food and Drug Administration” in the US for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. In solid cancer, targeting selectively one isoform of PI3-kinase may not be sufficient but association with other drugs used in chemotherapy or targeting specific proteins such as Poly (ADP-ribose) polymerase (PARP) could yield therapeutic benefits. Besides cancer, the PI3-kinase/Akt pathway also plays important roles in cardiovascular diseases. In 2012, cardiovascular diseases were responsible of 31% of all global deaths worldwide and more than 23 million people will die annually from these diseases by 2030. Among cardiovascular diseases, atherosclerosis and its thrombotic complications, including ischaemic heart disease and stroke, are major causes of mortality and new therapeutic options to treat these pathologies would be welcome. The mechanisms involved in the development of these diseases implicate a variety of signaling pathways and cell types, including endothelial cells, smooth muscle cells and platelets. Experimental models of cardiovascular diseases in genetically modified animals have provided proof-of-concept that class I PI3-kinase blockade can modify disease development and progression. Therapeutic inhibition of class I PI3-kinase isoforms constitutes promising strategies to restrain the development of atherosclerosis, prevent restenosis after angioplasty and stenting and blunt platelet aggregation to reduce arterial thrombotic risk. In this special issue of Advance in Biological Regulation, researchers from five teams working either in the field of pancreatic cancer or on cardiovascular diseases have critically discussed the implication of class I PI3-kinases signaling in these pathologies and its potential therapeutic targeting. Kriplani, Leslie and colleague have summarize our current knowledge of the class I PI3-kinase pathway components including kinases, downstream effectors of PtdIns(3,4,5)P3 and regulatory phosphatases. They also explored the evolutionary distribution of class I PI3-kinase pathway components and related this knowledge with their function. The apparent evolutionary conservation of many key actors of the PI3-kinase pathway likely reflects conserved functions from flies to mammals but also specialized roles in specific organisms and cells. Reconstruction of the evolutionary relationships among components of this pathway brings interesting information related to their roles in diseases and their potential status of drug targets. The implication of the PI3-kinase/Akt pathway in pancreatic cancer is discussed extensively in the reviews by Fitzgerald, McCubrey and colleagues and by Baer, Guilhermet and colleagues. Pancreatic cancer is a relatively common cancer which incidence is increasing. It is one of the most lethal cancers, with a 5-year death rate of 95% of diagnosed patients highlighting how new treatment options are urgently needed. Fitzgerald, McCubrey and colleagues discussed the role of the PI3-kinase/ Akt signaling pathway downstream of EGFR and KRAS in pancreatic cancer and in pancreatic cancer stem cells. Their detailed analysis focuses on recent advances in the complex and interconnected signaling circuitries found in these cancer cells and their therapeutic implications. In the review by Baer, Guilhermet and colleagues, the role of the different isoforms of PI3-kinase in oncogenesis is critically discussed as well as their importance in pancreatic ductal adenocarcinoma. The authors describe how the PI3kinase pathway plays a role both in the cancer cell but also in the tumor microenvironment. They also discuss about the therapeutic potential of targeting Class I PI3-kinase isoforms for pancreatic cancer treatment and the relevance of a strategy using isoform-specific inhibitors of PI3-kinases versus pan-PI3K inhibitors, considering potential adverse effects. In their review, Lupieri, Laffargue and colleagues discuss in detail the role of the different class I PI3-kinases in arterial diseases such as atherosclerosis and in restenosis after angioplasty. They describe their respective implication in endothelial cells, smooth muscle cells but also in the immune cells and highlight the highly-intertwined interactions between these cells in the development arterial wall diseases. This review also summarizes the rationale of PI3-kinase isoforms inhibition in the most prevalent cardiovascular diseases, and the available data on the therapeutic effects of PI3K inhibitors in preclinical models. Guidetti, Canobbio and Torti extensively discussed the implication of the different class I PI3K in blood platelet activation and more particularly their role in integrin signaling and in arterial thrombosis. Blood platelets are imperative to promptly arrest bleeding following vascular injury but upon rupture of an unstable atherosclerotic plaque, they form an occlusive thrombus (called atherothrombosis) preventing oxygen supply to brain or heart, which results in myocardial infarction or stroke. Patients with high risk for arterial thrombosis are treated with antiplatelet medications such as aspirin and clopidogrel. Although the current anti-platelet treatments do reduce the mortality and morbidity in different groups of patients, these treatments increase the bleeding risk. Therefore novel, improved anti-platelet therapies are needed. The authors of this review discuss the relevance of targeting class I PI3-kinase isoforms for future therapy to prevent arterial thrombosis without increasing the bleeding risk.
Please cite this article in press as: Payrastre, B., Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”, Advances in Biological Regulation (2015), http://dx.doi.org/10.1016/j.jbior.2015.07.001
B. Payrastre, L. Cocco / Advances in Biological Regulation xxx (2015) 1e3
3
Bernard Payrastre * INSERM UMR 1048, Institut des Maladies M etaboliques et Cardiovasculaires (I2MC), Universit e Toulouse III Paul Sabatier and Centre Hospitalier Universitaire de Toulouse, Laboratoire d'H ematologie, 1, Avenue Jean Poulh es BP 84225, 31432 Toulouse Cedex 4, France Lucio Cocco Cellular Signalling Laboratory, Department of Biomedical Sciences, University of Bologna, Via Irnerio, 48, I-40126 Bologna, Italy Corresponding author. E-mail address: [email protected] Available online xxx
Please cite this article in press as: Payrastre, B., Foreword: “The PI3-kinase/Akt pathway: From signaling to diseases”, Advances in Biological Regulation (2015), http://dx.doi.org/10.1016/j.jbior.2015.07.001