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Article: All over the place: deciphering HRAS signaling from different subcellular compartments.

Kolch, Walter / Matallanas, David

Molecular & cellular oncology

2019 Volume 6, Issue 5, Page(s) e1605821

Abstract: ... ...

Abstract	RAS
Language	English
Publishing date	2019-05-20
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2019.1605821
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Article: Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib.

Nolan, Aoife / Raso, Cinzia / Kolch, Walter / Kriegsheim, Alex von / Wynne, Kieran / Matallanas, David

Cancers

2023 Volume 15, Issue 16

Abstract: RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly ... ...

Abstract	RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in
Language	English
Publishing date	2023-08-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15164141
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Article: Multiple Myeloma Derived Extracellular Vesicle Uptake by Monocyte Cells Stimulates IL-6 and MMP-9 Secretion and Promotes Cancer Cell Migration and Proliferation.

Sheridan, Rebecca / Brennan, Kieran / Bazou, Despina / O'Gorman, Peter / Matallanas, David / Mc Gee, Margaret M

Cancers

2024 Volume 16, Issue 5

Abstract: Multiple Myeloma (MM) is an incurable haematological malignancy caused by uncontrolled growth of plasma cells. MM pathogenesis is attributed to crosstalk between plasma cells and the bone marrow microenvironment, where extracellular vesicles (EVs) play a ...

Abstract	Multiple Myeloma (MM) is an incurable haematological malignancy caused by uncontrolled growth of plasma cells. MM pathogenesis is attributed to crosstalk between plasma cells and the bone marrow microenvironment, where extracellular vesicles (EVs) play a role. In this study, EVs secreted from a panel of MM cell lines were isolated from conditioned media by ultracentrifugation and fluorescently stained EVs were co-cultured with THP-1 monocyte cells. MM EVs from three cell lines displayed a differential yet dose-dependent uptake by THP-1 cells, with H929 EVs displaying the greatest EV uptake compared to MM.1s and U266 EVs suggesting that uptake efficiency is dependent on the cell line of origin. Furthermore, MM EVs increased the secretion of MMP-9 and IL-6 from monocytes, with H929 EVs inducing the greatest effect, consistent with the greatest uptake efficiency. Moreover, monocyte-conditioned media collected following H929 EV uptake significantly increased the migration and proliferation of MM cells. Finally, EV proteome analysis revealed differential cargo enrichment that correlates with disease progression including a significant enrichment of spliceosome-related proteins in H929 EVs compared to the U266 and MM.1s EVs. Overall, this study demonstrates that MM-derived EVs modulate monocyte function to promote tumour growth and metastasis and reveals possible molecular mechanisms involved.
Language	English
Publishing date	2024-02-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16051011
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Article ; Online: The Ins and Outs of RAS Effector Complexes.

Kiel, Christina / Matallanas, David / Kolch, Walter

Biomolecules

2021 Volume 11, Issue 2

Abstract: RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these ... ...

Abstract	RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
MeSH term(s)	Computer Simulation ; Genes, ras ; Humans ; Molecular Structure ; Mutation ; Neoplasms/genetics ; Neoplasms/metabolism ; Precision Medicine ; Protein Binding ; Signal Transduction
Language	English
Publishing date	2021-02-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11020236
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Article ; Online: Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling.

Nolan, Aoife A / Aboud, Nourhan K / Kolch, Walter / Matallanas, David

Genes

2021 Volume 12, Issue 4

Abstract: Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling ... ...

Abstract	Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Carcinogenesis/drug effects ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Signal Transduction ; raf Kinases/genetics ; raf Kinases/metabolism ; ras Proteins/antagonists & inhibitors
Chemical Substances	Antineoplastic Agents ; raf Kinases (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2021-04-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes12040553
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Article ; Online: BAX and SMAC regulate bistable properties of the apoptotic caspase system.

McKenna, Stephanie / García-Gutiérrez, Lucía / Matallanas, David / Fey, Dirk

Scientific reports

2021 Volume 11, Issue 1, Page(s) 3272

Abstract: The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that ...

Abstract	The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch. Here we present a mathematical model of how BAX and SMAC control the apoptotic switch. Formulated as a system of ordinary differential equations, the model summarises experimental and computational evidence from the literature and incorporates the biochemical mechanisms of how BAX and SMAC interact with the components of the caspase system. Using simulations and bifurcation analysis, we find that both BAX and SMAC regulate the time-delay and activation threshold of the apoptotic switch. Interestingly, the model predicted that BAX (not SMAC) controls the amplitude of the apoptotic switch. Cell culture experiments using siRNA mediated BAX and SMAC knockdowns validated this model prediction. We further validated the model using data of the NCI-60 cell line panel using BAX protein expression as a cell-line specific parameter and show that model simulations correlated with the cellular response to DNA damaging drugs and established a defined threshold for caspase activation that could distinguish between sensitive and resistant melanoma cells. In summary, we present an experimentally validated dynamic model that summarises our current knowledge of how BAX and SMAC regulate the bistable properties of irreversible caspase activation during apoptosis.
MeSH term(s)	Antineoplastic Agents ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Caspases/metabolism ; HeLa Cells ; Humans ; Melanoma/drug therapy ; Melanoma/metabolism ; Mitochondrial Proteins/metabolism ; Models, Biological ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Antineoplastic Agents ; Apoptosis Regulatory Proteins ; BAX protein, human ; DIABLO protein, human ; Mitochondrial Proteins ; bcl-2-Associated X Protein ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2021-02-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-82215-2
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Article ; Online: Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner.

García-Gutiérrez, Lucía / Fallahi, Emma / Aboud, Nourhan / Quinn, Niall / Matallanas, David

Cell death & disease

2022 Volume 13, Issue 8, Page(s) 692

Abstract: Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 ... ...

Abstract	Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified the Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the antiapoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of apoptotic regulators that bind to SMAC and LATS1. Mechanistic analysis shows that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results in apoptosis. Importantly, we show that the oncogenic BRAF
MeSH term(s)	Apoptosis ; Caspases/metabolism ; Hippo Signaling Pathway ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Mitochondria/metabolism ; Protein Serine-Threonine Kinases/genetics ; Proteomics ; Proto-Oncogene Proteins B-raf/metabolism ; Serine-Threonine Kinase 3/metabolism
Chemical Substances	LATS1 protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; STK3 protein, human (EC 2.7.11.1) ; Serine-Threonine Kinase 3 (EC 2.7.11.1) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2022-08-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-022-05147-3
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Article ; Online: Cyclophilin A Isomerisation of Septin 2 Mediates Abscission during Cytokinesis.

Gorry, Rebecca L / Brennan, Kieran / Lavin, Paul T M / Mazurski, Tayler / Mary, Charline / Matallanas, David / Guichou, Jean-François / Mc Gee, Margaret M

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: The isomerase activity of Cyclophilin A is important for midbody abscission during cell division, however, to date, midbody substrates remain unknown. In this study, we report that the GTP-binding protein Septin 2 interacts with Cyclophilin A. We ... ...

Abstract	The isomerase activity of Cyclophilin A is important for midbody abscission during cell division, however, to date, midbody substrates remain unknown. In this study, we report that the GTP-binding protein Septin 2 interacts with Cyclophilin A. We highlight a dynamic series of Septin 2 phenotypes at the midbody, previously undescribed in human cells. Furthermore, Cyclophilin A depletion or loss of isomerase activity is sufficient to induce phenotypic Septin 2 defects at the midbody. Structural and molecular analysis reveals that Septin 2 proline 259 is important for interaction with Cyclophilin A. Moreover, an isomerisation-deficient EGFP-Septin 2 proline 259 mutant displays defective midbody localisation and undergoes impaired abscission, which is consistent with data from cells with loss of Cyclophilin A expression or activity. Collectively, these data reveal Septin 2 as a novel interacting partner and isomerase substrate of Cyclophilin A at the midbody that is required for abscission during cytokinesis in cancer cells.
MeSH term(s)	Humans ; Cytokinesis/genetics ; Septins/genetics ; Septins/metabolism ; Cyclophilin A/genetics ; Cyclophilin A/metabolism ; Cell Division ; HeLa Cells
Chemical Substances	Septins (EC 3.6.1.-) ; Cyclophilin A (EC 5.2.1.-)
Language	English
Publishing date	2023-07-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241311084
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Article ; Online: Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma.

Romano, David / García-Gutiérrez, Lucía / Aboud, Nourhan / Duffy, David J / Flaherty, Keith T / Frederick, Dennie T / Kolch, Walter / Matallanas, David

Life science alliance

2022 Volume 5, Issue 10

Abstract: The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with ... ...

Abstract	The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with BRAF
MeSH term(s)	Cell Line, Tumor ; Down-Regulation/genetics ; Drug Resistance, Neoplasm/genetics ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/metabolism ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/genetics
Chemical Substances	Protein Kinase Inhibitors ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2022-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201445
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Article: RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy.

García-Gutiérrez, Lucía / McKenna, Stephanie / Kolch, Walter / Matallanas, David

Cancers

2020 Volume 12, Issue 1

Abstract: The RASSF1A tumour suppressor is a scaffold protein that is involved in cell signalling. Increasing evidence shows that this protein sits at the crossroad of a complex signalling network, which includes key regulators of cellular homeostasis, such as Ras, ...

Abstract	The RASSF1A tumour suppressor is a scaffold protein that is involved in cell signalling. Increasing evidence shows that this protein sits at the crossroad of a complex signalling network, which includes key regulators of cellular homeostasis, such as Ras, MST2/Hippo, p53, and death receptor pathways. The loss of expression of RASSF1A is one of the most common events in solid tumours and is usually caused by gene silencing through DNA methylation. Thus, re-expression of RASSF1A or therapeutic targeting of effector modules of its complex signalling network, is a promising avenue for treating several tumour types. Here, we review the main modules of the RASSF1A signalling network and the evidence for the effects of network deregulation in different cancer types. In particular, we summarise the epigenetic mechanism that mediates RASSF1A promoter methylation and the Hippo and RAF1 signalling modules. Finally, we discuss different strategies that are described for re-establishing RASSF1A function and how a multitargeting pathway approach selecting druggable nodes in this network could lead to new cancer treatments.
Language	English
Publishing date	2020-01-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12010229
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