Publications by category
Journal articles
Bell AG, Thornber K, Chaput DL, Hasan NA, Mehedi Alam M, Haque MM, Cable J, Temperton B, Tyler CR (2023). Metagenomic assessment of the diversity and ubiquity of antimicrobial resistance genes in Bangladeshi aquaculture ponds. Aquaculture Reports, 29, 101462-101462.
Thornber K, Bashar A, Ahmed MS, Bell A, Trew J, Hasan M, Hasan NA, Alam MM, Chaput DL, Haque MM, et al (2022). Antimicrobial Resistance in Aquaculture Environments: Unravelling the Complexity and Connectivity of the Underlying Societal Drivers. Environmental Science & Technology, 56(21), 14891-14903.
Thornber K, Adshead F, Balayannis A, Brazier R, Brown R, Comber S, Court C, Davidson I, Depledge M, Farmer C, et al (2022). First, do no harm: time for a systems approach to address the problem of health-care-derived pharmaceutical pollution. The Lancet Planetary Health, 6(12), e935-e937.
Thornber K, Kirchhelle C (2022). Hardwiring antimicrobial resistance mitigation into global policy.
JAC Antimicrob Resist,
4(4).
Abstract:
Hardwiring antimicrobial resistance mitigation into global policy.
In the wake of COVID-19, antimicrobial resistance (AMR) has become termed the 'silent pandemic', with a growing number of editorials warning that international momentum for AMR mitigation is being lost amidst the global turmoil of COVID-19, economic crises and the climate emergency. Yet, is it sufficient to now simply turn the volume of the pre-existing AMR policy discourse back up? Although existing AMR initiatives have previously achieved high levels of international attention, their impact remains limited. We believe it is time to critically reflect on the achievements of the past 7 years and adapt our AMR policies based on the substantial literature and evidence base that exists on the socioecological drivers of AMR. We argue that developing a more sustainable and impactful response requires a shift away from framing AMR as a unique threat in competition with other global challenges. Instead, we need to move towards an approach that emphasizes AMR as inherently interlinked and consciously hardwires upstream interventions into broader global developmental agendas.
Abstract.
Author URL.
Thornber K, Pitchforth E (2021). Communicating antimicrobial resistance: the need to go beyond human health. JAC-antimicrobial resistance, 3(3).
Thornber K, Verner-Jeffreys D, Hinchliffe S, Rahman MM, Bass D, Tyler CR (2020). Evaluating antimicrobial resistance in the global shrimp industry.
Reviews in Aquaculture,
12(2), 966-986.
Abstract:
Evaluating antimicrobial resistance in the global shrimp industry
Antimicrobial resistance (AMR) is a growing threat to global public health, and the overuse of antibiotics in animals has been identified as a major risk factor. With high levels of international trade and direct connectivity to the aquatic environment, shrimp aquaculture may play a role in global AMR dissemination. The vast majority of shrimp production occurs in low- and middle-income countries, where antibiotic quality and usage is widely unregulated, and where the integration of aquaculture with family livelihoods offers many opportunities for human, animal and environmental bacteria to come into close contact. Furthermore, in shrimp growing areas, untreated waste is often directly eliminated into local water sources. These risks are very different to many other major internationally-traded aquaculture commodities, such as salmon, which is produced in higher income countries where there are greater levels of regulation and well-established management practices. Assessing the true scale of the risk of AMR dissemination in the shrimp industry is a considerable challenge, not least because obtaining reliable data on antibiotic usage is very difficult. Combating the risks associated with AMR dissemination is also challenging due to the increasing trend towards intensification and its associated disease burden, and because many farmers currently have no alternatives to antibiotics for preventing crop failure. In this review, we critically assess the potential risks the shrimp industry poses to AMR dissemination. We also discuss some of the possible risk mitigation strategies that could be considered by the shrimp industry as it strives for a more sustainable future in production.
Abstract.
Thornber K, Huso D, Rahman MM, Biswas H, Rahman MH, Brum E, Tyler CR (2019). Raising awareness of antimicrobial resistance in rural aquaculture practice in Bangladesh through digital communications: a pilot study.
Glob Health Action,
12(sup1).
Abstract:
Raising awareness of antimicrobial resistance in rural aquaculture practice in Bangladesh through digital communications: a pilot study.
One of the key strategic objectives of the World Health Organisation's global antimicrobial resistance (AMR) action plan is to improve public awareness and understanding of this issue. Very few AMR awareness campaigns have targeted the animal production sector, particularly in low- and middle-income countries (LMICs) where rural communities can be geographically difficult to access via traditional face-to-face community engagement methods. Aquaculture is a major food production industry in Bangladesh and across Asia, an area which poses a significant risk to global AMR dissemination. In this pilot study, we sought to investigate the potential for digital communication materials to rapidly and effectively communicate AMR messages to rural aquaculture farmers in Bangladesh. Working with stakeholders from the Bangladesh aquaculture industry, we developed a 4-minute digital animation designed specifically for this audience and assessed its capacity to engage and communicate AMR messages to farmers. We then conducted a small-scale social media campaign, to determine the potential for rapidly disseminating AMR awareness materials to a large audience across Bangladesh, where there is an extensive 4 G internet network and an ever-increasing proportion of the population (57% as of December 2019) have mobile internet access. Thirty-six farmers were surveyed: all of them liked this method of communication and 97% said it would change the way they use antibiotics in the future. Through the social media campaign, the animation received 9,100 views in the first 2 weeks alone. Although preliminary, these results demonstrate the huge potential for digital communication methods for the rapid and widespread communication of AMR awareness materials to rural aquaculture communities in Bangladesh and across Asia. Our results support the need for more research into the most appropriate and effective content of AMR awareness campaigns for aquaculture communities and question the need for explaining the science underlying AMR in such communication materials.
Abstract.
Author URL.
Colomba A, Giuriato S, Dejean E, Thornber K, Delsol G, Tronchère H, Meggetto F, Payrastre B, Gaits-Iacovoni F (2011). Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination.
Blood Cancer J,
1(6).
Abstract:
Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM-ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM-ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.
Abstract.
Author URL.
Thornber K, Colomba A, Ceccato L, Delsol G, Payrastre B, Gaits-Iacovoni F (2009). Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.
Oncogene,
28(29), 2690-2696.
Abstract:
Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.
The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active. Consistent with this, NDGA treatment resulted in the inhibition of key pathways, such as Akt, signal transducer and activator of transcription factor 3 (STAT3) and extracellular signal-regulated kinase (ERK), which are involved in NPM-ALK antiapoptotic and pro-mitogenic functions. Conversely, the stress-activated kinase p38, described in some instances as a mediator of apoptosis, was activated. Interestingly, 5-LOX, an isoform involved in many cancers, was found to be activated in NPM-ALK(+) cells. Functional studies have shown that transforming properties, namely proliferation and resistance to apoptosis, were abrogated by treatment with either NDGA or the 5-LOX inhibitor (N-(3-phenoxycinnamyl)-acetohydroxamic acid) (BW A4C). Together, these data point to the ROS/LOX pathway as a potential new target for therapy in NPM-ALK-positive tumors.
Abstract.
Author URL.
Pears CJ, Thornber K, Auger JM, Hughes CE, Grygielska B, Protty MB, Pearce AC, Watson SP (2008). Differential roles of the PKC novel isoforms, PKCdelta and PKCepsilon, in mouse and human platelets.
PLoS One,
3(11).
Abstract:
Differential roles of the PKC novel isoforms, PKCdelta and PKCepsilon, in mouse and human platelets.
BACKGROUND: Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation. METHODOLOGY/PRINCIPAL FINDINGS: in this study, we focus on the role of two novel PKC isoforms, PKCdelta and PKCepsilon, in both mouse and human platelets. PKCdelta is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKCdelta undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKCepsilon, is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKCepsilon in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcRgamma-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor. CONCLUSIONS: These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms delta and epsilon in human and mouse platelets and a selective role for PKCepsilon in signalling through GPVI.
Abstract.
Author URL.
Thornber K, McCarty OJT, Watson SP, Pears CJ (2006). Distinct but critical roles for integrin alphaIIbbeta3 in platelet lamellipodia formation on fibrinogen, collagen-related peptide and thrombin.
FEBS J,
273(22), 5032-5043.
Abstract:
Distinct but critical roles for integrin alphaIIbbeta3 in platelet lamellipodia formation on fibrinogen, collagen-related peptide and thrombin.
Integrins are the major receptor type known to facilitate cell adhesion and lamellipodia formation on extracellular matrix proteins. However, collagen-related peptide and thrombin have recently been shown to mediate platelet lamellipodia formation when presented as immobilized surfaces. The aims of this study were to establish if there exists a role for the platelet integrin alpha(IIb)beta(3) in this response; and if so, whether signalling from the integrin is required for lamellipodia formation on these surfaces. Real-time analysis was used to compare platelet morphological changes on surfaces of fibrinogen, collagen-related peptide or thrombin in the presence of various pharmacological inhibitors and platelets from 'knockout' mice. We demonstrate that collagen-related peptide and thrombin stimulate distinct patterns of platelet lamellipodia formation and elevation of intracellular Ca(2+) to that induced by the integrin alpha(IIb)beta(3) ligand, fibrinogen. Nevertheless, lamellipodia formation on collagen-related peptide and thrombin is dependent upon engagement of alpha(IIb)beta(3), consistent with release of alpha(IIb)beta(3) ligand(s) from platelet granules. However, the requirement for signalling by the integrin on fibrinogen can be bypassed by the addition of thrombin to the solution. These observations reveal a critical role for alpha(IIb)beta(3) in forming lamellipodia on collagen-related peptide and thrombin which is dependent on its ability to function as an adhesive receptor but not necessarily on its ability to signal. These results suggest that integrins may play an important role in lamellipodia formation triggered by nonintegrin ligands in platelets and possibly in other cell types.
Abstract.
Author URL.
Publications by year
In Press
Bell AG, Thornber K, Chaput DL, Hasan NA, Alam MM, Haque MM, Cable J, Temperton B, Tyler CR (In Press). The Diversity and Ubiquity of Antibiotic Resistance Genes in Finfish Culture Ponds in Bangladesh.
Abstract:
The Diversity and Ubiquity of Antibiotic Resistance Genes in Finfish Culture Ponds in Bangladesh
AbstractIn Bangladesh, fish provide over 60% of animal-source food with 56.2% of this coming from aquaculture produced predominantly in rural freshwater ponds. Increasing demand for fish products is driving intensification and resulting in higher disease prevalence, posing a risk to food security. Biosecurity is often absent in rural aquaculture practices in Bangladesh and antibiotics are commonly used to treat and prevent disease outbreaks. Antibiotics are often administered incorrectly - a key factor associated with the development of antimicrobial resistance (AMR). AMR can be disseminated rapidly within microbial ecosystems via mobile genetic elements, posing a risk for humans and animals infected with AMR pathogens as treatments with antibiotics become ineffective. Early AMR detection and understanding of the spread of antimicrobial resistant genes (ARGs) in rural aquaculture practices is critical for both food security and human health protection. Here, we apply a metagenomic approach to assess the ARG composition in pond water from six finfish (tilapia and pangasius) farms in the Mymensingh division of North-central Bangladesh. We found microbial communities within the ponds had similar alpha and beta diversities, with multiple ARGs predicted to confer resistance to eighteen different classes of antimicrobials. The most common ARGs conferred resistance to aminoglycosides and sulphonamides and were present in taxa associated with both fish and human pathogens. This ARG diversity potentially confers resistance to a wide variety of antibiotic classes and questions the effectiveness of current and future treatment of diseases with antibiotics in earthen aquaculture ponds. The microbial and ARG compositions between fish ponds within each farm were similar, which may relate to parallels in farming practices creating similar microbial selection pressures and thus comparable microbial populations. Without a more controlled approach towards antibiotic usage, will inevitably further exacerbate the challenges in treating and preventing disease outbreaks as aquaculture production intensifies in Bangladesh.HighlightsARGs in Bangladesh rural fishponds indicate resistance to 18 different antibioticsThe most common AMR were to aminoglycosides and sulphonamidesARGs were present in plasmids and taxa-associated pathogensFarming practices strongly influence microbial and ARG compositionsIdentified ARGs question antibiotic treatment of disease in rural aquaculture
Abstract.
2023
Bell AG, Thornber K, Chaput DL, Hasan NA, Mehedi Alam M, Haque MM, Cable J, Temperton B, Tyler CR (2023). Metagenomic assessment of the diversity and ubiquity of antimicrobial resistance genes in Bangladeshi aquaculture ponds. Aquaculture Reports, 29, 101462-101462.
2022
Thornber K, Bashar A, Ahmed MS, Bell A, Trew J, Hasan M, Hasan NA, Alam MM, Chaput DL, Haque MM, et al (2022). Antimicrobial Resistance in Aquaculture Environments: Unravelling the Complexity and Connectivity of the Underlying Societal Drivers. Environmental Science & Technology, 56(21), 14891-14903.
Thornber K, Adshead F, Balayannis A, Brazier R, Brown R, Comber S, Court C, Davidson I, Depledge M, Farmer C, et al (2022). First, do no harm: time for a systems approach to address the problem of health-care-derived pharmaceutical pollution. The Lancet Planetary Health, 6(12), e935-e937.
Thornber K, Kirchhelle C (2022). Hardwiring antimicrobial resistance mitigation into global policy.
JAC Antimicrob Resist,
4(4).
Abstract:
Hardwiring antimicrobial resistance mitigation into global policy.
In the wake of COVID-19, antimicrobial resistance (AMR) has become termed the 'silent pandemic', with a growing number of editorials warning that international momentum for AMR mitigation is being lost amidst the global turmoil of COVID-19, economic crises and the climate emergency. Yet, is it sufficient to now simply turn the volume of the pre-existing AMR policy discourse back up? Although existing AMR initiatives have previously achieved high levels of international attention, their impact remains limited. We believe it is time to critically reflect on the achievements of the past 7 years and adapt our AMR policies based on the substantial literature and evidence base that exists on the socioecological drivers of AMR. We argue that developing a more sustainable and impactful response requires a shift away from framing AMR as a unique threat in competition with other global challenges. Instead, we need to move towards an approach that emphasizes AMR as inherently interlinked and consciously hardwires upstream interventions into broader global developmental agendas.
Abstract.
Author URL.
2021
Thornber K, Pitchforth E (2021). Communicating antimicrobial resistance: the need to go beyond human health. JAC-antimicrobial resistance, 3(3).
2020
Thornber K, Verner-Jeffreys D, Hinchliffe S, Rahman MM, Bass D, Tyler CR (2020). Evaluating antimicrobial resistance in the global shrimp industry.
Reviews in Aquaculture,
12(2), 966-986.
Abstract:
Evaluating antimicrobial resistance in the global shrimp industry
Antimicrobial resistance (AMR) is a growing threat to global public health, and the overuse of antibiotics in animals has been identified as a major risk factor. With high levels of international trade and direct connectivity to the aquatic environment, shrimp aquaculture may play a role in global AMR dissemination. The vast majority of shrimp production occurs in low- and middle-income countries, where antibiotic quality and usage is widely unregulated, and where the integration of aquaculture with family livelihoods offers many opportunities for human, animal and environmental bacteria to come into close contact. Furthermore, in shrimp growing areas, untreated waste is often directly eliminated into local water sources. These risks are very different to many other major internationally-traded aquaculture commodities, such as salmon, which is produced in higher income countries where there are greater levels of regulation and well-established management practices. Assessing the true scale of the risk of AMR dissemination in the shrimp industry is a considerable challenge, not least because obtaining reliable data on antibiotic usage is very difficult. Combating the risks associated with AMR dissemination is also challenging due to the increasing trend towards intensification and its associated disease burden, and because many farmers currently have no alternatives to antibiotics for preventing crop failure. In this review, we critically assess the potential risks the shrimp industry poses to AMR dissemination. We also discuss some of the possible risk mitigation strategies that could be considered by the shrimp industry as it strives for a more sustainable future in production.
Abstract.
2019
Thornber K, Huso D, Rahman MM, Biswas H, Rahman MH, Brum E, Tyler CR (2019). Raising awareness of antimicrobial resistance in rural aquaculture practice in Bangladesh through digital communications: a pilot study.
Glob Health Action,
12(sup1).
Abstract:
Raising awareness of antimicrobial resistance in rural aquaculture practice in Bangladesh through digital communications: a pilot study.
One of the key strategic objectives of the World Health Organisation's global antimicrobial resistance (AMR) action plan is to improve public awareness and understanding of this issue. Very few AMR awareness campaigns have targeted the animal production sector, particularly in low- and middle-income countries (LMICs) where rural communities can be geographically difficult to access via traditional face-to-face community engagement methods. Aquaculture is a major food production industry in Bangladesh and across Asia, an area which poses a significant risk to global AMR dissemination. In this pilot study, we sought to investigate the potential for digital communication materials to rapidly and effectively communicate AMR messages to rural aquaculture farmers in Bangladesh. Working with stakeholders from the Bangladesh aquaculture industry, we developed a 4-minute digital animation designed specifically for this audience and assessed its capacity to engage and communicate AMR messages to farmers. We then conducted a small-scale social media campaign, to determine the potential for rapidly disseminating AMR awareness materials to a large audience across Bangladesh, where there is an extensive 4 G internet network and an ever-increasing proportion of the population (57% as of December 2019) have mobile internet access. Thirty-six farmers were surveyed: all of them liked this method of communication and 97% said it would change the way they use antibiotics in the future. Through the social media campaign, the animation received 9,100 views in the first 2 weeks alone. Although preliminary, these results demonstrate the huge potential for digital communication methods for the rapid and widespread communication of AMR awareness materials to rural aquaculture communities in Bangladesh and across Asia. Our results support the need for more research into the most appropriate and effective content of AMR awareness campaigns for aquaculture communities and question the need for explaining the science underlying AMR in such communication materials.
Abstract.
Author URL.
2011
Colomba A, Giuriato S, Dejean E, Thornber K, Delsol G, Tronchère H, Meggetto F, Payrastre B, Gaits-Iacovoni F (2011). Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination.
Blood Cancer J,
1(6).
Abstract:
Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM-ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM-ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas.
Abstract.
Author URL.
2009
Thornber K, Colomba A, Ceccato L, Delsol G, Payrastre B, Gaits-Iacovoni F (2009). Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.
Oncogene,
28(29), 2690-2696.
Abstract:
Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.
The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active. Consistent with this, NDGA treatment resulted in the inhibition of key pathways, such as Akt, signal transducer and activator of transcription factor 3 (STAT3) and extracellular signal-regulated kinase (ERK), which are involved in NPM-ALK antiapoptotic and pro-mitogenic functions. Conversely, the stress-activated kinase p38, described in some instances as a mediator of apoptosis, was activated. Interestingly, 5-LOX, an isoform involved in many cancers, was found to be activated in NPM-ALK(+) cells. Functional studies have shown that transforming properties, namely proliferation and resistance to apoptosis, were abrogated by treatment with either NDGA or the 5-LOX inhibitor (N-(3-phenoxycinnamyl)-acetohydroxamic acid) (BW A4C). Together, these data point to the ROS/LOX pathway as a potential new target for therapy in NPM-ALK-positive tumors.
Abstract.
Author URL.
2008
Pears CJ, Thornber K, Auger JM, Hughes CE, Grygielska B, Protty MB, Pearce AC, Watson SP (2008). Differential roles of the PKC novel isoforms, PKCdelta and PKCepsilon, in mouse and human platelets.
PLoS One,
3(11).
Abstract:
Differential roles of the PKC novel isoforms, PKCdelta and PKCepsilon, in mouse and human platelets.
BACKGROUND: Increasing evidence suggests that individual isoforms of protein kinase C (PKC) play distinct roles in regulating platelet activation. METHODOLOGY/PRINCIPAL FINDINGS: in this study, we focus on the role of two novel PKC isoforms, PKCdelta and PKCepsilon, in both mouse and human platelets. PKCdelta is robustly expressed in human platelets and undergoes transient tyrosine phosphorylation upon stimulation by thrombin or the collagen receptor, GPVI, which becomes sustained in the presence of the pan-PKC inhibitor, Ro 31-8220. In mouse platelets, however, PKCdelta undergoes sustained tyrosine phosphorylation upon activation. In contrast the related isoform, PKCepsilon, is expressed at high levels in mouse but not human platelets. There is a marked inhibition in aggregation and dense granule secretion to low concentrations of GPVI agonists in mouse platelets lacking PKCepsilon in contrast to a minor inhibition in response to G protein-coupled receptor agonists. This reduction is mediated by inhibition of tyrosine phosphorylation of the FcRgamma-chain and downstream proteins, an effect also observed in wild-type mouse platelets in the presence of a PKC inhibitor. CONCLUSIONS: These results demonstrate a reciprocal relationship in levels of the novel PKC isoforms delta and epsilon in human and mouse platelets and a selective role for PKCepsilon in signalling through GPVI.
Abstract.
Author URL.
2006
Thornber K, McCarty OJT, Watson SP, Pears CJ (2006). Distinct but critical roles for integrin alphaIIbbeta3 in platelet lamellipodia formation on fibrinogen, collagen-related peptide and thrombin.
FEBS J,
273(22), 5032-5043.
Abstract:
Distinct but critical roles for integrin alphaIIbbeta3 in platelet lamellipodia formation on fibrinogen, collagen-related peptide and thrombin.
Integrins are the major receptor type known to facilitate cell adhesion and lamellipodia formation on extracellular matrix proteins. However, collagen-related peptide and thrombin have recently been shown to mediate platelet lamellipodia formation when presented as immobilized surfaces. The aims of this study were to establish if there exists a role for the platelet integrin alpha(IIb)beta(3) in this response; and if so, whether signalling from the integrin is required for lamellipodia formation on these surfaces. Real-time analysis was used to compare platelet morphological changes on surfaces of fibrinogen, collagen-related peptide or thrombin in the presence of various pharmacological inhibitors and platelets from 'knockout' mice. We demonstrate that collagen-related peptide and thrombin stimulate distinct patterns of platelet lamellipodia formation and elevation of intracellular Ca(2+) to that induced by the integrin alpha(IIb)beta(3) ligand, fibrinogen. Nevertheless, lamellipodia formation on collagen-related peptide and thrombin is dependent upon engagement of alpha(IIb)beta(3), consistent with release of alpha(IIb)beta(3) ligand(s) from platelet granules. However, the requirement for signalling by the integrin on fibrinogen can be bypassed by the addition of thrombin to the solution. These observations reveal a critical role for alpha(IIb)beta(3) in forming lamellipodia on collagen-related peptide and thrombin which is dependent on its ability to function as an adhesive receptor but not necessarily on its ability to signal. These results suggest that integrins may play an important role in lamellipodia formation triggered by nonintegrin ligands in platelets and possibly in other cell types.
Abstract.
Author URL.
