IgG1s produced by cell culture are heterogeneous with respect to their afucosylated Fc glycan content. Since afucosylation content dramatically changes the nature of IgG1s, there exists a need for methods capable to dissecting the contributions of the different afucosylated IgG1 forms to biological activity. Recently, Zhan and Chung applied classical ligand-receptor mathematical analysis to receptor binding data obtained from heterogeneous mixtures of afucosylated IgG1s in order to develop methods capable of performing such operations [1] . By explaining important experimental observations and extracting valuable biochemical property information embedded in the data, their model provides a convincing demonstration of the role that mechanistic mathematical modeling can play in characterizing heterogeneous mixtures of complex molecules. This review highlights important features of their mathematical analysis from a drug development perspective.
{"title":"Computational Characterization of Afucosylation-Based IgG1 Heterogeneity","authors":"John D. Chung, P. Zhan","doi":"10.14800/RCI.758","DOIUrl":"https://doi.org/10.14800/RCI.758","url":null,"abstract":"IgG1s produced by cell culture are heterogeneous with respect to their afucosylated Fc glycan content. Since afucosylation content dramatically changes the nature of IgG1s, there exists a need for methods capable to dissecting the contributions of the different afucosylated IgG1 forms to biological activity. Recently, Zhan and Chung applied classical ligand-receptor mathematical analysis to receptor binding data obtained from heterogeneous mixtures of afucosylated IgG1s in order to develop methods capable of performing such operations [1] . By explaining important experimental observations and extracting valuable biochemical property information embedded in the data, their model provides a convincing demonstration of the role that mechanistic mathematical modeling can play in characterizing heterogeneous mixtures of complex molecules. This review highlights important features of their mathematical analysis from a drug development perspective.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83164781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Saxena, B. Jha, A. S. Meena, H. Narula, Davendra Kumar, S. Naqvi
Sheep is considered to be short day seasonal breeder. Sheep does show varying behavior in terms of seasonal reproduction between temperate and tropical latitudinal regions. MTNR1A gene has been studied widely for being linked to seasonality in sheep. Recently, through our studies we have characterized the MTNR1A gene in Tropical arid sheep breeds and could find out that the GG and CC genotypes are having higher prevalence in the tropical arid breed populationwith reference to two SNP markers ‘ ‘G612A’ and C606T’ respectively.
{"title":"Melatonin Receptor 1A (MTNR1A) gene sequence characterization and SNP identification in Tropical sheep breeds of India","authors":"V. Saxena, B. Jha, A. S. Meena, H. Narula, Davendra Kumar, S. Naqvi","doi":"10.14800/RCI.731","DOIUrl":"https://doi.org/10.14800/RCI.731","url":null,"abstract":"Sheep is considered to be short day seasonal breeder. Sheep does show varying behavior in terms of seasonal reproduction between temperate and tropical latitudinal regions. MTNR1A gene has been studied widely for being linked to seasonality in sheep. Recently, through our studies we have characterized the MTNR1A gene in Tropical arid sheep breeds and could find out that the GG and CC genotypes are having higher prevalence in the tropical arid breed populationwith reference to two SNP markers ‘ ‘G612A’ and C606T’ respectively.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91481480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Membrane cholesterol can alter the signaling pathways of living cells. However, the process that modulates the interaction of receptor proteins is still unclear. We performed single-molecule optical tracking of ligand-induced dimerization of epidermal growth factor receptors (EGFRs) in two cancerous cell lines (HeLa and A431) and one normal endothelial cell line (MCF12A). We discovered that unliganded EGFRs typically reside in non-raft regions of the plasma membrane and can move into raft domains upon ligand binding. This ligand-induced motion could be a common behavior in live cells. We found that the amount of membrane cholesterol significantly affects the stability of EGFR dimers by manipulating the total amount of membrane cholesterol with methyl-β-cyclodextrin and the local concentration of cholesterol with nystatin. The EGFR dimers in the plasma membrane of normal cells are more sensitive to changes in the local concentration of cholesterol compared with the cancer cells. Our methodology can yield useful information for understanding cholesterol-mediated protein-protein interactions in live cells.
{"title":"Unraveling the mechanism of cholesterol-mediated regulation of receptor dimerization in plasma membranes in vivo","authors":"Jung Y. Huang, Chien Y. Lin, L. Lo","doi":"10.14800/RCI.684","DOIUrl":"https://doi.org/10.14800/RCI.684","url":null,"abstract":"Membrane cholesterol can alter the signaling pathways of living cells. However, the process that modulates the interaction of receptor proteins is still unclear. We performed single-molecule optical tracking of ligand-induced dimerization of epidermal growth factor receptors (EGFRs) in two cancerous cell lines (HeLa and A431) and one normal endothelial cell line (MCF12A). We discovered that unliganded EGFRs typically reside in non-raft regions of the plasma membrane and can move into raft domains upon ligand binding. This ligand-induced motion could be a common behavior in live cells. We found that the amount of membrane cholesterol significantly affects the stability of EGFR dimers by manipulating the total amount of membrane cholesterol with methyl-β-cyclodextrin and the local concentration of cholesterol with nystatin. The EGFR dimers in the plasma membrane of normal cells are more sensitive to changes in the local concentration of cholesterol compared with the cancer cells. Our methodology can yield useful information for understanding cholesterol-mediated protein-protein interactions in live cells.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90854749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years Alzheimer’s disease (AD) has emerged as a research priority mainly due to an impressive increase in the average life expectancy in humans, which is associated with debilitating neurodegenerative disorders. The cardinal feature of the disease is accumulation of the amyloid-β peptide, which is derived from the sequential proteolytic cleavage of the amyloid precursor protein (APP). SorLA (sorting protein-related receptor with A-type repeats) is a member of the VPS10p-domain receptor gene family and identified as a significant sorting receptor that controls the processing and trafficking of APP. This review systematically discusses information on sorLA associations with AD including the mechanisms that regulate sorLA activity. We also describe how advances in understanding the mechanisms by which sorLA can reduce the amyloidogenic pathway may open for novel therapeutic strategies in tackling this devastating disorder.
{"title":"Associations of sorLA/SORL1 with Alzheimer's disease","authors":"Ishita Guha Thakurta, O. Andersen","doi":"10.14800/RCI.700","DOIUrl":"https://doi.org/10.14800/RCI.700","url":null,"abstract":"In recent years Alzheimer’s disease (AD) has emerged as a research priority mainly due to an impressive increase in the average life expectancy in humans, which is associated with debilitating neurodegenerative disorders. The cardinal feature of the disease is accumulation of the amyloid-β peptide, which is derived from the sequential proteolytic cleavage of the amyloid precursor protein (APP). SorLA (sorting protein-related receptor with A-type repeats) is a member of the VPS10p-domain receptor gene family and identified as a significant sorting receptor that controls the processing and trafficking of APP. This review systematically discusses information on sorLA associations with AD including the mechanisms that regulate sorLA activity. We also describe how advances in understanding the mechanisms by which sorLA can reduce the amyloidogenic pathway may open for novel therapeutic strategies in tackling this devastating disorder.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"168 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78020763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Long-term clinical adjuvant antihormone therapy for breast cancer has significantly improved survival of estrogen receptor (ER)-positive breast cancer patients, but acquired resistance to antiestrogens is a major challenge in clinic. The evolution of acquired resistance to selective estrogen receptor modulators (SERMs) is unique because the growth of resistant tumors is dependent on SERMs. Thus, it appears that acquired resistance to SERMs is initially able to utilize either estrogen (E 2 ) or a SERM as the growth stimulus in the ER-positive SERM-resistant breast tumors. However, no mechanism has been established to explain this paradox. Our newly established cell model MCF-7: PF, for the first time, replicates Phase I acquired resistance to SERMs in vitro . The cells are stimulated to grow robustly with E 2 and SERMs through the ER which is confirmed by the evidence that pure antiestrogen ICI 182,780 (ICI) completely blocks the stimulation induced by E 2 or SERMs. In contrast to E 2 that activates classical ER-target genes, SERMs continue to function as effective antiestrogens to inhibit classical ER-target genes, even at the time of growth stimulation. A significant alteration of ER function observed in SERM-resistant cells is the enhancement of the non-genomic pathway of ER and the activation of multiple membrane function-associated molecules including focal adhesion molecules and adapter proteins to further increase phosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Inhibition of membrane-associated signaling, IGF-1R and focal adhesion kinase (FAK), completely abolishes 4-OHT-stimulated cell growth. Overall, the constant nuclear pressure causes broad activation of membrane-associated signaling to aid breast cancer cell survival during the selection process required for acquired SERM resistance. The targeting of these membrane function-associated pathways and seeking new unanticipated combination therapies may have further clinical potential to decipher and treat endocrine-resistant breast cancer.
{"title":"The function of membrane-associated molecules in acquired resistance to antiestrogens in breast cancer","authors":"P. Fan, V. Jordan","doi":"10.14800/RCI.703","DOIUrl":"https://doi.org/10.14800/RCI.703","url":null,"abstract":"Long-term clinical adjuvant antihormone therapy for breast cancer has significantly improved survival of estrogen receptor (ER)-positive breast cancer patients, but acquired resistance to antiestrogens is a major challenge in clinic. The evolution of acquired resistance to selective estrogen receptor modulators (SERMs) is unique because the growth of resistant tumors is dependent on SERMs. Thus, it appears that acquired resistance to SERMs is initially able to utilize either estrogen (E 2 ) or a SERM as the growth stimulus in the ER-positive SERM-resistant breast tumors. However, no mechanism has been established to explain this paradox. Our newly established cell model MCF-7: PF, for the first time, replicates Phase I acquired resistance to SERMs in vitro . The cells are stimulated to grow robustly with E 2 and SERMs through the ER which is confirmed by the evidence that pure antiestrogen ICI 182,780 (ICI) completely blocks the stimulation induced by E 2 or SERMs. In contrast to E 2 that activates classical ER-target genes, SERMs continue to function as effective antiestrogens to inhibit classical ER-target genes, even at the time of growth stimulation. A significant alteration of ER function observed in SERM-resistant cells is the enhancement of the non-genomic pathway of ER and the activation of multiple membrane function-associated molecules including focal adhesion molecules and adapter proteins to further increase phosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Inhibition of membrane-associated signaling, IGF-1R and focal adhesion kinase (FAK), completely abolishes 4-OHT-stimulated cell growth. Overall, the constant nuclear pressure causes broad activation of membrane-associated signaling to aid breast cancer cell survival during the selection process required for acquired SERM resistance. The targeting of these membrane function-associated pathways and seeking new unanticipated combination therapies may have further clinical potential to decipher and treat endocrine-resistant breast cancer.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84105408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Bjerregaard-Olesen, E. Bonefeld‐Jørgensen
Perfluorinated alkyl acids (PFAAs) are used in many household products including food contact materials. Hence, humans are continuously exposed, and the PFAAs are accumulated in human serum with half-lives up to 8.8 years. In humans, high PFAA serum levels have been associated with an increased risk of breast cancer and other adverse health effects such as lower birth weight and longer time to pregnancy which might be related to disruptions of various hormonal systems. For instance, direct cell exposure studies in vitro suggest that some PFAAs can transactivate the estrogen receptor (ER), antagonize the androgen receptor (AR) and has the potential to interfere with TH and AhR functions. Moreover, the PFAAs also showed cellular oxidative stress. Humans are exposed to an array of PFAAs, and the quantity and combination of these PFAAs in human serum differs between individuals. Hence, the toxicological studies of single PFAAs and simple mixtures might be insufficient to predict how the actual mixtures of PFAAs may affect humans. To get a better evaluation of the actual mixture effects, we developed a method to extract the actual mixture of PFAAs from human serum. Preliminary results showed that 17% of the PFAA serum fractions from pregnant women could significantly transactivate the ER, and 94% of the fractions could further increase the transactivity induced by the potent ER ligand 25 pM 17β-estradiol. As part of the international FETOTOX project ( http://fetotox.au.dk/ ), we are currently extracting the actual PFAA serum mixture from 700 pregnant women to further elucidate whether the serum PFAA mixture can transactivate the ER at the levels found in human serum. We suggest that our method can in the future be used to study the actual serum PFAA mixture effects on both steroid hormone actions as well as other hormonal systems e.g. thyroid hormone function. In the current review we will discuss how our recently developed PFAA extraction method might be used in future research to assess the endocrine impact of PFAAs on human health.
{"title":"Receptor research on xenohormone effects of human serum extracts containing the actual mixture of perfluorinated alkyl acids: a short review","authors":"Christian Bjerregaard-Olesen, E. Bonefeld‐Jørgensen","doi":"10.14800/RCI.702","DOIUrl":"https://doi.org/10.14800/RCI.702","url":null,"abstract":"Perfluorinated alkyl acids (PFAAs) are used in many household products including food contact materials. Hence, humans are continuously exposed, and the PFAAs are accumulated in human serum with half-lives up to 8.8 years. In humans, high PFAA serum levels have been associated with an increased risk of breast cancer and other adverse health effects such as lower birth weight and longer time to pregnancy which might be related to disruptions of various hormonal systems. For instance, direct cell exposure studies in vitro suggest that some PFAAs can transactivate the estrogen receptor (ER), antagonize the androgen receptor (AR) and has the potential to interfere with TH and AhR functions. Moreover, the PFAAs also showed cellular oxidative stress. Humans are exposed to an array of PFAAs, and the quantity and combination of these PFAAs in human serum differs between individuals. Hence, the toxicological studies of single PFAAs and simple mixtures might be insufficient to predict how the actual mixtures of PFAAs may affect humans. To get a better evaluation of the actual mixture effects, we developed a method to extract the actual mixture of PFAAs from human serum. Preliminary results showed that 17% of the PFAA serum fractions from pregnant women could significantly transactivate the ER, and 94% of the fractions could further increase the transactivity induced by the potent ER ligand 25 pM 17β-estradiol. As part of the international FETOTOX project ( http://fetotox.au.dk/ ), we are currently extracting the actual PFAA serum mixture from 700 pregnant women to further elucidate whether the serum PFAA mixture can transactivate the ER at the levels found in human serum. We suggest that our method can in the future be used to study the actual serum PFAA mixture effects on both steroid hormone actions as well as other hormonal systems e.g. thyroid hormone function. In the current review we will discuss how our recently developed PFAA extraction method might be used in future research to assess the endocrine impact of PFAAs on human health.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72865516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Gu, M. Lovelace, M. Weible, D. Allen, S. Eamegdool, J. Wiley
The expression and function of P2X7 receptors in adult CNS have been widely studied, however, the roles of these purinergic receptors in human neural development has largely focused on the effects of receptor activation. Previous studies of embryonic and adult rodent neural precursors suggest adenosine triphosphate (ATP), the physiological agonist for P2X receptors, can act as a potent modifier of proliferation, migration and differentiation, mediated via intracellular calcium ([Ca 2+ ] i ) signaling. The P2X7 receptor has a ubiquitous distribution in the body but is most abundant on macrophages and microglia where its activation by ATP leads to secretion of proinflammatory cytokines. However, extracellular ATP concentrations in the CNS are usually at sub-micromolar levels suggesting that ATP-induced activation of the P2X7 receptor will not occur under physiological circumstances in the CNS. Another possible role for P2X7 receptors has been suggested by recent work on macrophages and neural precursor cells. In these studies the P2X7 receptor was shown to act as a scavenger receptor i.e. a receptor present on a phagocytotic cell which detects molecules present on the surface of apoptotic cells and facilitates phagocytosis of the apoptotic cell. In a recent study of human neural precursor cells (hNPCs) and neuroblasts isolated from human fetal telencephalons at 16-19 WG, our group showed that both P2X7R high /DCX low hNPCs and P2X7R high /DCX high neuroblasts were capable of phagocytic engulfment of a range of targets including latex beads, apoptotic ReN cells and apoptotic neuroblasts. We found that these neuroblasts and their precursor cells expressed functional P2X7 receptors on their cell surface. Although expression of P2X7 is widespread in the cells of the neuroblast, it is those DCX + neuroblasts with the highest expression of P2X7 which are actively phagocytic towards an autologous apoptotic neighbour or other phagocytic targets, including latex beads and apoptotic ReNcells. Pre-incubation of P2X7 high neuroblasts with ATP or oxidized ATP inhibited phagocytosis of targets by these cells. Moreover siRNA knockdown of P2X7R also inhibited phagocytosis of the apoptotic targets. This review considers this major new role for the P2X7 receptor in early human neurogenesis.
{"title":"P2X7 is an archaic scavenger receptor recognizing apoptotic neuroblasts in early human neurogenesis","authors":"B. Gu, M. Lovelace, M. Weible, D. Allen, S. Eamegdool, J. Wiley","doi":"10.14800/RCI.699","DOIUrl":"https://doi.org/10.14800/RCI.699","url":null,"abstract":"The expression and function of P2X7 receptors in adult CNS have been widely studied, however, the roles of these purinergic receptors in human neural development has largely focused on the effects of receptor activation. Previous studies of embryonic and adult rodent neural precursors suggest adenosine triphosphate (ATP), the physiological agonist for P2X receptors, can act as a potent modifier of proliferation, migration and differentiation, mediated via intracellular calcium ([Ca 2+ ] i ) signaling. The P2X7 receptor has a ubiquitous distribution in the body but is most abundant on macrophages and microglia where its activation by ATP leads to secretion of proinflammatory cytokines. However, extracellular ATP concentrations in the CNS are usually at sub-micromolar levels suggesting that ATP-induced activation of the P2X7 receptor will not occur under physiological circumstances in the CNS. Another possible role for P2X7 receptors has been suggested by recent work on macrophages and neural precursor cells. In these studies the P2X7 receptor was shown to act as a scavenger receptor i.e. a receptor present on a phagocytotic cell which detects molecules present on the surface of apoptotic cells and facilitates phagocytosis of the apoptotic cell. In a recent study of human neural precursor cells (hNPCs) and neuroblasts isolated from human fetal telencephalons at 16-19 WG, our group showed that both P2X7R high /DCX low hNPCs and P2X7R high /DCX high neuroblasts were capable of phagocytic engulfment of a range of targets including latex beads, apoptotic ReN cells and apoptotic neuroblasts. We found that these neuroblasts and their precursor cells expressed functional P2X7 receptors on their cell surface. Although expression of P2X7 is widespread in the cells of the neuroblast, it is those DCX + neuroblasts with the highest expression of P2X7 which are actively phagocytic towards an autologous apoptotic neighbour or other phagocytic targets, including latex beads and apoptotic ReNcells. Pre-incubation of P2X7 high neuroblasts with ATP or oxidized ATP inhibited phagocytosis of targets by these cells. Moreover siRNA knockdown of P2X7R also inhibited phagocytosis of the apoptotic targets. This review considers this major new role for the P2X7 receptor in early human neurogenesis.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72685624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rictor is a cytosolic protein that was originally recognized as a specific component of the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). This complex integrates nutrient- and growth factor-induced signaling cascades to regulate cell proliferation and metabolism. An increasing body of evidence however shows that rictor may also function independently of mTORC2 through association with other proteins and complexes. Recent studies on mast cells demonstrated that in the context of mTORC2 rictor positively regulates proliferation of immature and migration of mature mast cells whereas by itself rictor independently functions as a molecular relay that sets the sensitivity of high affinity receptor for IgE (FceRI) for activating mast cell degranulation. These novel findings suggest that rictor is a multifunctional protein that plays a role in synchronization of multiple cellular functions in mast cells.
{"title":"Rictor beyond the TORC: linking the proliferation, migration and FcεRI-mediated degranulation of human mast cells","authors":"P. Taborska, J. Bartunkova, D. Smrz","doi":"10.14800/RCI.686","DOIUrl":"https://doi.org/10.14800/RCI.686","url":null,"abstract":"Rictor is a cytosolic protein that was originally recognized as a specific component of the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). This complex integrates nutrient- and growth factor-induced signaling cascades to regulate cell proliferation and metabolism. An increasing body of evidence however shows that rictor may also function independently of mTORC2 through association with other proteins and complexes. Recent studies on mast cells demonstrated that in the context of mTORC2 rictor positively regulates proliferation of immature and migration of mature mast cells whereas by itself rictor independently functions as a molecular relay that sets the sensitivity of high affinity receptor for IgE (FceRI) for activating mast cell degranulation. These novel findings suggest that rictor is a multifunctional protein that plays a role in synchronization of multiple cellular functions in mast cells.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85536126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The known physiological effect of angiotensin II (AngII) type I receptors (AT 1 Rs), synthesis and secretion of the cardiotoxic hormone aldosterone, whose elevation accompanies and aggravates heart failure (HF), is mediated by both G proteins and barrestins (barrs). We recently examined the relative potencies of all the currently used in the clinic AT 1 R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of either of these two signaling mediators at the AngII-bound AT 1 R and, consequently, at suppression of aldosterone in vitro and in vivo. We also tested the impact of the aldosterone suppression they produce in vivo on the cardiac function of post-myocardial infarction (MI) animals progressing to HF. By using a variety of techniques in cultured cells in vitro, we found that all ARBs are potent inhibitors of G protein activation at the AT 1 R but display striking differences in their potency at blocking the second signaling component of aldosterone production in the adrenal cortex, i.e. barrs. Candesartan and valsartan in particular were found the most potent at blocking AngII-induced barr activation at this receptor, translating into excellent efficacies at aldosterone suppression in vitro and in vivo and at post-MI cardiac function and remodeling amelioration. Conversely, irbesartan appears to be largely G protein- inhibitory, as it exhibits very low potency towards barr inhibition. As a result, it is a very weak aldosterone suppressor in vitro and in vivo, and fails to improve cardiac function or adverse remodeling post-MI. These findings will aid pharmacotherapeutic decisions for therapy of post-MI HF and they will also help develop novel and better ARB drugs, with greater efficacy for HF therapy.
{"title":"Which ARB drug is better for heart failure therapy? Aldosterone suppression holds the answer","authors":"K. McCrink, Ava R. Brill, A. Lymperopoulos","doi":"10.14800/RCI.690","DOIUrl":"https://doi.org/10.14800/RCI.690","url":null,"abstract":"The known physiological effect of angiotensin II (AngII) type I receptors (AT 1 Rs), synthesis and secretion of the cardiotoxic hormone aldosterone, whose elevation accompanies and aggravates heart failure (HF), is mediated by both G proteins and barrestins (barrs). We recently examined the relative potencies of all the currently used in the clinic AT 1 R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of either of these two signaling mediators at the AngII-bound AT 1 R and, consequently, at suppression of aldosterone in vitro and in vivo. We also tested the impact of the aldosterone suppression they produce in vivo on the cardiac function of post-myocardial infarction (MI) animals progressing to HF. By using a variety of techniques in cultured cells in vitro, we found that all ARBs are potent inhibitors of G protein activation at the AT 1 R but display striking differences in their potency at blocking the second signaling component of aldosterone production in the adrenal cortex, i.e. barrs. Candesartan and valsartan in particular were found the most potent at blocking AngII-induced barr activation at this receptor, translating into excellent efficacies at aldosterone suppression in vitro and in vivo and at post-MI cardiac function and remodeling amelioration. Conversely, irbesartan appears to be largely G protein- inhibitory, as it exhibits very low potency towards barr inhibition. As a result, it is a very weak aldosterone suppressor in vitro and in vivo, and fails to improve cardiac function or adverse remodeling post-MI. These findings will aid pharmacotherapeutic decisions for therapy of post-MI HF and they will also help develop novel and better ARB drugs, with greater efficacy for HF therapy.","PeriodicalId":20980,"journal":{"name":"Receptors and clinical investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83061878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Giovannelli, M. D. Donato, G. Cernera, A. Santi, G. Galasso, E. D. Zazzo, Flavia Vitale, G. Castoria, A. Migliaccio
The androgen receptor (AR) mediates differentiation, proliferation and transformation of target tissues. These processes require a crosstalk between epithelial and stromal cells. Prostate cancer (PCa) represents a major cause of cancer-related mortality in men, and is often associated with deregulation of androgen/AR axis. Clinical and molecular findings have highlighted the role of epithelial AR in PCa progression. In contrast, the functions of AR in mesenchymal cells are still unclear. We previously reported that low androgen concentration (1 pM) triggers interaction of AR with the Src tyrosine kinase and PI3-K, thus driving cell cycle progression in fibroblasts. In contrast, stimulation of fibroblasts and fibrosarcoma cells with physiological (10 nM) androgen concentration leads to interaction of AR with full-length filamin A (FLNa) and does not trigger DNA synthesis. On the basis of these findings, we re-examined the role of androgen/AR axis in fibroblasts and human fibrosarcoma HT1080 cells. Recently, we obtained two original and integrated findings on the decision of mesenchymal cells to undergo reversible quiescence and migrate upon stimulation with 10 nM androgens (Castoria et al. 2011 and 2014). This decision is dependent upon the interaction of AR with FLNa. Once assembled, the bipartite AR/FLNa complex recruits a1-integrin and triggers Rac1 activation, thereby enhancing on the one hand cell motility. On the other, Rac 1 activation triggers its downstream effector DYRK 1B, which phosphorylates Ser10 of p27. Stabilization of p27 and cell quiescence then follow. These results strengthen and extend our studies, adding a new and exciting piece to the complex puzzle of signaling networks activated by androgens in target cells. Our findings might have implications for current approaches to AR-related diseases.
雄激素受体(AR)介导靶组织的分化、增殖和转化。这些过程需要上皮细胞和基质细胞之间的串扰。前列腺癌(PCa)是男性癌症相关死亡的主要原因，通常与雄激素/AR轴的失调有关。临床和分子研究结果强调了上皮性AR在前列腺癌进展中的作用。相比之下，AR在间充质细胞中的功能尚不清楚。我们之前报道过低雄激素浓度(1pm)会触发AR与Src酪氨酸激酶和PI3-K的相互作用，从而驱动成纤维细胞的细胞周期进程。相反，用生理(10 nM)雄激素浓度刺激成纤维细胞和纤维肉瘤细胞会导致AR与全长丝蛋白A (FLNa)相互作用，而不会触发DNA合成。基于这些发现，我们重新研究了雄激素/AR轴在成纤维细胞和人纤维肉瘤HT1080细胞中的作用。最近，我们获得了两个关于间充质细胞在10 nM雄激素刺激下进行可逆静止和迁移的决定的原始和完整的发现(Castoria et al. 2011和2014)。这一决定取决于AR与FLNa的相互作用。AR/FLNa复合体一旦组装，就会招募a1-整合素并触发Rac1激活，从而一方面增强细胞的运动性。另一方面，Rac 1激活触发其下游效应物DYRK 1B，使p27的Ser10磷酸化。随后是p27的稳定和细胞的静息。这些结果加强和扩展了我们的研究，为靶细胞中雄激素激活的信号网络的复杂谜题增加了一个新的和令人兴奋的部分。我们的研究结果可能对目前治疗ar相关疾病的方法有所启示。
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