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Article ; Online: Publisher's Note: ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase.

Hoxhaj, Gerta / Najafov, Ayaz / Toth, Rachel / Campbell, David G / Prescott, Alan R / MacKintosh, Carol

2022 Volume 135, Issue 6

Language	English
Publishing date	2022-03-10
Publishing country	England
Document type	Published Erratum
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.259936
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Article: Recent advances in understanding the roles of whole genome duplications in evolution.

MacKintosh, Carol / Ferrier, David E K

F1000Research

2017 Volume 6, Page(s) 1623

Abstract: Ancient whole-genome duplications (WGDs)- ...

Abstract	Ancient whole-genome duplications (WGDs)-
Language	English
Publishing date	2017-08-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2699932-8
ISSN	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.11792.2
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Article ; Online: Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells.

Murugesan, Gavuthami / Prescott, Alan R / Toth, Rachel / Campbell, David G / Wells, Claire M / MacKintosh, Carol

The Biochemical journal

2022 Volume 479, Issue 16, Page(s) 1709–1725

Abstract: The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic ...

Abstract	The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non-synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regulation of the sister kinases and their roles in melanoma cells. In common with many ohnologue protein kinases, PAK4, PAK5 and PAK6 each have two 14-3-3-binding phosphosites of which phosphoSer99 is conserved. PAK4 localises to the leading edge of cells in response to phorbol ester-stimulated binding of 14-3-3 to phosphoSer99 and phosphoSer181, which are phosphorylated by two different PKCs or PKDs. These phosphorylations of PAK4 are essential for its phorbol ester-stimulated phosphorylation of downstream substrates. In contrast, 14-3-3 interacts with PAK5 in response to phorbol ester-stimulated phosphorylation of Ser99 and epidermal growth factor-stimulated phosphorylation of Ser288; whereas PAK6 docks onto 14-3-3 and is prevented from localising to cell-cell junctions when Ser133 is phosphorylated in response to cAMP-elevating agents via PKA and insulin-like growth factor 1 via PKB/Akt. Silencing of PAK4 impairs viability, migration and invasive behaviour of melanoma cells carrying BRAFV600E or NRASQ61K mutations. These defects are rescued by ectopic expression of PAK4, more so by a 14-3-3-binding deficient PAK4, and barely by PAK5 or PAK6. Together these genomic, biochemical and cellular data suggest that the oncogenic properties of PAK4 are regulated by PKC-PKD signalling in melanoma, while PAK5 and PAK6 are dispensable in this cancer.
MeSH term(s)	Humans ; Melanoma/genetics ; Phorbol Esters ; Phosphorylation ; Protein Kinases/metabolism ; p21-Activated Kinases/genetics ; p21-Activated Kinases/metabolism
Chemical Substances	Phorbol Esters ; Protein Kinases (EC 2.7.-) ; PAK4 protein, human (EC 2.7.1.11) ; PAK6 protein, human (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-08-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20220184
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Article ; Online: Experiences of health care for older people who need support to live at home: A systematic review of the qualitative literature.

Gregory, Anna / Mackintosh, Shylie / Kumar, Saravana / Grech, Carol

Geriatric nursing (New York, N.Y.)

2017 Volume 38, Issue 4, Page(s) 315–324

Abstract: Perceived experiences of health care for older people who need support to live at home can illuminate areas needing improvement in quality of care, and guide towards better ways to support ageing populations to live at home. This systematic review ... ...

Abstract	Perceived experiences of health care for older people who need support to live at home can illuminate areas needing improvement in quality of care, and guide towards better ways to support ageing populations to live at home. This systematic review synthesized findings from the qualitative literature about perceived experiences of health care for older people who need support to live at home, from the perceptions of older people, carers and health providers. Searches of electronic databases and eligibility screening produced 46 included studies for review. Thematic synthesis revealed how health care impacts on the older person's sense of autonomy, both in health care decisions and everyday life. Autonomy is empowered by the older person's own capacity and by respectful conduct of health providers. Engagement between older people, carers and health providers is a negotiated interaction, affected by multiple factors.
MeSH term(s)	Aged ; Caregivers/psychology ; Home Care Services/utilization ; Humans ; Qualitative Research ; Quality of Health Care
Language	English
Publishing date	2017-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	632559-2
ISSN	1528-3984 ; 0197-4572
ISSN (online)	1528-3984
ISSN	0197-4572
DOI	10.1016/j.gerinurse.2016.12.001
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Article ; Online: Visibility and meanings of partnership in health care for older people who need support to live at home.

Gregory, Anna / Mackintosh, Shylie / Kumar, Saravana / Grech, Carol

Scandinavian journal of caring sciences

2017 Volume 32, Issue 3, Page(s) 1027–1037

Abstract: Introduction: Problems experienced by older people with complex needs to live at home have been reported in the literature. This qualitative study builds on previous research and investigates enduring issues older people face when interacting with ... ...

Abstract	Introduction: Problems experienced by older people with complex needs to live at home have been reported in the literature. This qualitative study builds on previous research and investigates enduring issues older people face when interacting with healthcare services. Aim: To gain an in-depth understanding of what is involved in providing good quality health care for older people who need support to live at home. Methodological design: We adopted an interpretive descriptive approach and conducted semi-structured interviews with older people (n = 7), carers (n = 8) and key informants (n = 11). Initial and secondary analysis of qualitative data was completed. Findings: Major themes emerged about meanings of partnership in health care, and invisibility of the older person as a partner in health care. Partnership in health care was understood to mean being treated as an equal, being involved in decision-making, and making contributions which impact on health care and health systems. The metaphorical concept of 'invisibility' related to the older person not being seen and heard as a partner in health care, as well as being a recipient of care. Conclusions: We concluded that older people who need support to live at home are not highly visible to health providers, policymakers and researchers as a central partner and consumer to be meaningfully engaged in shaping their health care. Opportunities to address persistent issues with quality of health care may in future be achieved through stronger partnerships between older people and health providers, to find new ways to improve the quality of care for older people.
MeSH term(s)	Aged ; Aged, 80 and over ; Caregivers/psychology ; Female ; Frail Elderly/psychology ; Home Care Services/organization & administration ; Humans ; Male ; Middle Aged ; Patient-Centered Care/organization & administration ; Quality of Health Care/organization & administration ; South Australia
Language	English
Publishing date	2017-11-24
Publishing country	Sweden
Document type	Journal Article
ZDB-ID	639217-9
ISSN	1471-6712 ; 0283-9318
ISSN (online)	1471-6712
ISSN	0283-9318
DOI	10.1111/scs.12545
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Article ; Online: Recent advances in understanding the roles of whole genome duplications in evolution [version 2; referees

Carol MacKintosh / David E.K. Ferrier

F1000Research, Vol

2 approved]

2018 Volume 6

Abstract: Ancient whole-genome duplications (WGDs)—paleopolyploidy events—are key to solving Darwin’s ‘abominable mystery’ of how flowering plants evolved and radiated into a rich variety of species. The vertebrates also emerged from their invertebrate ancestors ... ...

Abstract	Ancient whole-genome duplications (WGDs)—paleopolyploidy events—are key to solving Darwin’s ‘abominable mystery’ of how flowering plants evolved and radiated into a rich variety of species. The vertebrates also emerged from their invertebrate ancestors via two WGDs, and genomes of diverse gymnosperm trees, unicellular eukaryotes, invertebrates, fishes, amphibians and even a rodent carry evidence of lineage-specific WGDs. Modern polyploidy is common in eukaryotes, and it can be induced, enabling mechanisms and short-term cost-benefit assessments of polyploidy to be studied experimentally. However, the ancient WGDs can be reconstructed only by comparative genomics: these studies are difficult because the DNA duplicates have been through tens or hundreds of millions of years of gene losses, mutations, and chromosomal rearrangements that culminate in resolution of the polyploid genomes back into diploid ones (rediploidisation). Intriguing asymmetries in patterns of post-WGD gene loss and retention between duplicated sets of chromosomes have been discovered recently, and elaborations of signal transduction systems are lasting legacies from several WGDs. The data imply that simpler signalling pathways in the pre-WGD ancestors were converted via WGDs into multi-stranded parallelised networks. Genetic and biochemical studies in plants, yeasts and vertebrates suggest a paradigm in which different combinations of sister paralogues in the post-WGD regulatory networks are co-regulated under different conditions. In principle, such networks can respond to a wide array of environmental, sensory and hormonal stimuli and integrate them to generate phenotypic variety in cell types and behaviours. Patterns are also being discerned in how the post-WGD signalling networks are reconfigured in human cancers and neurological conditions. It is fascinating to unpick how ancient genomic events impact on complexity, variety and disease in modern life.
Keywords	Agriculture & Biotechnology ; Community Ecology & Biodiversity ; Developmental Evolution ; Evolutionary/Comparative Genetics ; Evolutionary Ecology ; Genomics ; Microbial Evolution & Genomics ; Plant Biochemistry & Physiology ; Plant-Biotic Interactions ; Plant Genetics & Gene Expression ; Plant Genomes & Evolution ; Plant Growth & Development ; Medicine ; R ; Science ; Q
Subject code	570 ; 580
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes.

Mackintosh, Carol

The Biochemical journal

2004 Volume 381, Issue Pt 2, Page(s) 329–342

Abstract: 14-3-3 proteins exert an extraordinarily widespread influence on cellular processes in all eukaryotes. They operate by binding to specific phosphorylated sites on diverse target proteins, thereby forcing conformational changes or influencing interactions ...

Abstract	14-3-3 proteins exert an extraordinarily widespread influence on cellular processes in all eukaryotes. They operate by binding to specific phosphorylated sites on diverse target proteins, thereby forcing conformational changes or influencing interactions between their targets and other molecules. In these ways, 14-3-3s 'finish the job' when phosphorylation alone lacks the power to drive changes in the activities of intracellular proteins. By interacting dynamically with phosphorylated proteins, 14-3-3s often trigger events that promote cell survival--in situations from preventing metabolic imbalances caused by sudden darkness in leaves to mammalian cell-survival responses to growth factors. Recent work linking specific 14-3-3 isoforms to genetic disorders and cancers, and the cellular effects of 14-3-3 agonists and antagonists, indicate that the cellular complement of 14-3-3 proteins may integrate the specificity and strength of signalling through to different cellular responses.
MeSH term(s)	14-3-3 Proteins/chemistry ; 14-3-3 Proteins/metabolism ; Animals ; Cell Physiological Phenomena ; Humans ; Phosphoproteins/chemistry ; Phosphoproteins/metabolism ; Protein Interaction Mapping ; Protein Structure, Quaternary/physiology
Chemical Substances	14-3-3 Proteins ; Phosphoproteins
Language	English
Publishing date	2004-07-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20031332
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Article ; Online: AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours.

Ross, Fiona A / MacKintosh, Carol / Hardie, D Grahame

The FEBS journal

2016 Volume 283, Issue 16, Page(s) 2987–3001

Abstract: The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in essentially all eukaryotic cells, suggesting that it arose during early eukaryotic evolution. It occurs universally as heterotrimeric complexes containing ... ...

Abstract	The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in essentially all eukaryotic cells, suggesting that it arose during early eukaryotic evolution. It occurs universally as heterotrimeric complexes containing catalytic α subunits and regulatory β and γ subunits. Although Drosophila melanogaster contains single genes encoding each subunit, in mammals, each subunit exists as multiple isoforms encoded by distinct genes, giving rise to up to 12 heterotrimeric combinations. The multiple isoforms of each subunit are 2R-ohnologues generated by the two rounds of whole genome duplication that occurred at the evolutionary origin of the vertebrates. Although the differential roles of these isoform combinations remain only partly understood, there are indications that they may have different subcellular locations, different inputs and outputs, and different functions. The multiple isoforms are of particular interest with respect to the roles of AMPK in cancer because the genes encoding some isoforms, such as PRKAA1 and PRKAB2 (encoding α1 and β2), are quite frequently amplified in tumour cells, whereas the genes encoding others, such as PRKAA2 (encoding α2), tend to be mutated, which, in some but not all cases, may result in a loss of function. Thus, although AMPK acts downstream of the tumour suppressor liver kinase B1, and some of its isoform combinations may act as tumour suppressors that restrain the growth and proliferation of tumour cells, other isoform combinations may paradoxically act as oncogenes, perhaps by aiding the survival of tumour cells undergoing environmental stresses such as hypoxia or nutrient deprivation.
MeSH term(s)	AMP-Activated Protein Kinases/chemistry ; AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; AMP-Activated Protein Kinases/physiology ; Animals ; Evolution, Molecular ; Humans ; Isoenzymes/genetics ; Neoplasms/enzymology ; Oncogene Proteins/metabolism ; Protein Subunits/chemistry ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Isoenzymes ; Oncogene Proteins ; Protein Subunits ; Tumor Suppressor Proteins ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2016-03-24
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.13698
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Article ; Online: Recent advances in understanding the roles of whole genome duplications in evolution [version 1; referees

Carol MacKintosh / David E.K. Ferrier

F1000Research, Vol

2 approved]

2017 Volume 6

Abstract	Ancient whole-genome duplications (WGDs)—paleopolyploidy events—are key to solving Darwin’s ‘abominable mystery’ of how flowering plants evolved and radiated into a rich variety of species. The vertebrates also emerged from their invertebrate ancestors via two WGDs, and genomes of diverse gymnosperm trees, unicellular eukaryotes, invertebrates, fishes, amphibians and even a rodent carry evidence of lineage-specific WGDs. Modern polyploidy is common in eukaryotes, and it can be induced, enabling mechanisms and short-term cost-benefit assessments of polyploidy to be studied experimentally. However, the ancient WGDs can be reconstructed only by comparative genomics: these studies are difficult because the DNA duplicates have been through tens or hundreds of millions of years of gene losses, mutations, and chromosomal rearrangements that culminate in resolution of the polyploid genomes back into diploid ones (rediploidisation). Intriguing asymmetries in patterns of post-WGD gene loss and retention between duplicated sets of chromosomes have been discovered recently, and elaborations of signal transduction systems are lasting legacies from several WGDs. The data imply that simpler signalling pathways in the pre-WGD ancestors were converted via WGDs into multi-stranded parallelised networks. Genetic and biochemical studies in plants, yeasts and vertebrates suggest a paradigm in which different combinations of sister paralogues in the post-WGD regulatory networks are co-regulated under different conditions. In principle, such networks can respond to a wide array of environmental, sensory and hormonal stimuli and integrate them to generate phenotypic variety in cell types and behaviours. Patterns are also being discerned in how the post-WGD signalling networks are reconfigured in human cancers and neurological conditions. It is fascinating to unpick how ancient genomic events impact on complexity, variety and disease in modern life.
Keywords	Agriculture & Biotechnology ; Community Ecology & Biodiversity ; Developmental Evolution ; Evolutionary/Comparative Genetics ; Evolutionary Ecology ; Genomics ; Microbial Evolution & Genomics ; Plant Biochemistry & Physiology ; Plant-Biotic Interactions ; Plant Genetics & Gene Expression ; Plant Genomes & Evolution ; Plant Growth & Development ; Medicine ; R ; Science ; Q
Subject code	570 ; 580
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.

Munier, Claire C / De Maria, Leonardo / Edman, Karl / Gunnarsson, Anders / Longo, Marianna / MacKintosh, Carol / Patel, Saleha / Snijder, Arjan / Wissler, Lisa / Brunsveld, Luc / Ottmann, Christian / Perry, Matthew W D

The Journal of biological chemistry

2021 Volume 296, Page(s) 100551

Abstract: The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that plays a central role in inflammation. The GR activity is also modulated via protein-protein interactions, including binding of 14-3-3 proteins induced by GR phosphorylation. ...

Abstract	The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that plays a central role in inflammation. The GR activity is also modulated via protein-protein interactions, including binding of 14-3-3 proteins induced by GR phosphorylation. However, the specific phosphorylation sites on the GR that trigger these interactions and their functional consequences are less clear. Hence, we sought to examine this system in more detail. We used phosphorylated GR peptides, biophysical studies, and X-ray crystallography to identify key residues within the ligand-binding domain of the GR, T524 and S617, whose phosphorylation results in binding of the representative 14-3-3 protein 14-3-3ζ. A kinase screen identified misshapen-like kinase 1 (MINK1) as responsible for phosphorylating T524 and Rho-associated protein kinase 1 for phosphorylating S617; cell-based approaches confirmed the importance of both GR phosphosites and MINK1 but not Rho-associated protein kinase 1 alone in inducing GR-14-3-3 binding. Together our results provide molecular-level insight into 14-3-3-mediated regulation of the GR and highlight both MINK1 and the GR-14-3-3 axis as potential targets for future therapeutic intervention.
MeSH term(s)	14-3-3 Proteins/genetics ; 14-3-3 Proteins/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Mutation ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism ; Threonine/genetics ; Threonine/metabolism ; Transcriptional Activation
Chemical Substances	14-3-3 Proteins ; Receptors, Glucocorticoid ; Threonine (2ZD004190S) ; MINK1 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.100551
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