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Article: Novel insights into the RTK-dependent metastatic phenotype of KRAS-mutant lung adenocarcinoma.

Cooke, Mariana

Molecular & cellular oncology

2021 Volume 8, Issue 6, Page(s) 2013723

Abstract: In a recent study, our group identified RAC guanine nucleotide exchange factors (RAC-GEFs) driving motility signaling in KRAS mutant lung adenocarcinoma cells. The RAC-GEFs FARP1, ARHGEF39 and TIAM2 play fundamental roles in the formation of membrane ... ...

Abstract	In a recent study, our group identified RAC guanine nucleotide exchange factors (RAC-GEFs) driving motility signaling in KRAS mutant lung adenocarcinoma cells. The RAC-GEFs FARP1, ARHGEF39 and TIAM2 play fundamental roles in the formation of membrane ruffles in response to growth factor receptor stimulation.
Language	English
Publishing date	2021-12-14
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2021.2013723
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Article ; Online: Protein kinase C signaling "in" and "to" the nucleus: Master kinases in transcriptional regulation.

Kazanietz, Marcelo G / Cooke, Mariana

The Journal of biological chemistry

2024 Volume 300, Issue 3, Page(s) 105692

Abstract: PKC is a multifunctional family of Ser-Thr kinases widely implicated in the regulation of fundamental cellular functions, including proliferation, polarity, motility, and differentiation. Notwithstanding their primary cytoplasmic localization and ... ...

Abstract	PKC is a multifunctional family of Ser-Thr kinases widely implicated in the regulation of fundamental cellular functions, including proliferation, polarity, motility, and differentiation. Notwithstanding their primary cytoplasmic localization and stringent activation by cell surface receptors, PKC isozymes impel prominent nuclear signaling ultimately impacting gene expression. While transcriptional regulation may be wielded by nuclear PKCs, it most often relies on cytoplasmic phosphorylation events that result in nuclear shuttling of PKC downstream effectors, including transcription factors. As expected from the unique coupling of PKC isozymes to signaling effector pathways, glaring disparities in gene activation/repression are observed upon targeting individual PKC family members. Notably, specific PKCs control the expression and activation of transcription factors implicated in cell cycle/mitogenesis, epithelial-to-mesenchymal transition and immune function. Additionally, PKCs isozymes tightly regulate transcription factors involved in stepwise differentiation of pluripotent stem cells toward specific epithelial, mesenchymal, and hematopoietic cell lineages. Aberrant PKC expression and/or activation in pathological conditions, such as in cancer, leads to profound alterations in gene expression, leading to an extensive rewiring of transcriptional networks associated with mitogenesis, invasiveness, stemness, and tumor microenvironment dysregulation. In this review, we outline the current understanding of PKC signaling "in" and "to" the nucleus, with significant focus on established paradigms of PKC-mediated transcriptional control. Dissecting these complexities would allow the identification of relevant molecular targets implicated in a wide spectrum of diseases.
MeSH term(s)	Gene Expression Regulation/genetics ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Signal Transduction ; Transcription Factors/metabolism ; Humans ; Animals ; Cell Nucleus/enzymology ; Cell Nucleus/genetics
Chemical Substances	Isoenzymes ; Protein Kinase C (EC 2.7.11.13) ; Transcription Factors
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.105692
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Article ; Online: Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity.

Cooke, Mariana / Kazanietz, Marcelo G

Science signaling

2022 Volume 15, Issue 729, Page(s) eabo0264

Abstract: Diacylglycerol (DAG) is a lipid second messenger that is generated in response to extracellular stimuli and channels intracellular signals that affect mammalian cell proliferation, survival, and motility. DAG exerts a myriad of biological functions ... ...

Abstract	Diacylglycerol (DAG) is a lipid second messenger that is generated in response to extracellular stimuli and channels intracellular signals that affect mammalian cell proliferation, survival, and motility. DAG exerts a myriad of biological functions through protein kinase C (PKC) and other effectors, such as protein kinase D (PKD) isozymes and small GTPase-regulating proteins (such as RasGRPs). Imbalances in the fine-tuned homeostasis between DAG generation by phospholipase C (PLC) enzymes and termination by DAG kinases (DGKs), as well as dysregulation in the activity or abundance of DAG effectors, have been widely associated with tumor initiation, progression, and metastasis. DAG is also a key orchestrator of T cell function and thus plays a major role in tumor immunosurveillance. In addition, DAG pathways shape the tumor ecosystem by arbitrating the complex, dynamic interaction between cancer cells and the immune landscape, hence representing powerful modifiers of immune checkpoint and adoptive T cell-directed immunotherapy. Exploiting the wide spectrum of DAG signals from an integrated perspective could underscore meaningful advances in targeted cancer therapy.
MeSH term(s)	Animals ; Diacylglycerol Kinase/metabolism ; Diglycerides/metabolism ; Ecosystem ; Mammals/metabolism ; Neoplasms/therapy ; Signal Transduction
Chemical Substances	Diglycerides ; Diacylglycerol Kinase (EC 2.7.1.107)
Language	English
Publishing date	2022-04-12
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.abo0264
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Article ; Online: Protocol for fluorescence-activated cell sorting of human EpCAM

Sullivan, Neil T / Cooke, Mariana

STAR protocols

2022 Volume 3, Issue 2, Page(s) 101367

Abstract: Here, we describe a protocol for fluorescence-activated cell sorting (FACS) of human ... ...

Abstract	Here, we describe a protocol for fluorescence-activated cell sorting (FACS) of human EpCAM
MeSH term(s)	Epithelial Cell Adhesion Molecule/genetics ; Flow Cytometry/methods ; Gene Expression ; Guanine ; Guanine Nucleotide Exchange Factors ; Humans ; Lung Neoplasms/genetics ; Nucleotides
Chemical Substances	EPCAM protein, human ; Epithelial Cell Adhesion Molecule ; Guanine Nucleotide Exchange Factors ; Nucleotides ; Guanine (5Z93L87A1R)
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101367
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Article: ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1.

Aljagthmi, Amjad A / Hira, Akshay / Zhang, Jin / Cooke, Mariana / Kazanietz, Marcelo G / Kadakia, Madhavi P

Cell death discovery

2024 Volume 10, Issue 1, Page(s) 13

Abstract: ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in maintaining the proliferative potential of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexpressed in ... ...

Abstract	ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in maintaining the proliferative potential of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexpressed in squamous cell carcinoma, loss of ΔNp63α expression is associated with increased tumor cell invasion and metastasis. We recently identified a ΔNp63α/miR-320a/PKCγ signaling axis that regulates cancer cell invasion by inhibiting phosphorylation of the small GTPase Rac1, a master switch of cell motility that positively regulates cell invasion in multiple human cancers. In this study, we identified a novel mechanism by which ΔNp63α negatively regulates Rac1 activity, by inhibiting the expression of the Rac-specific Guanine Exchange Factor PREX1. ΔNp63α knockdown in multiple squamous cell carcinoma cell lines leads to increased Rac1 activation, which is abrogated by treatment with the Rac1 inhibitor NSC23766. Furthermore, ΔNp63α negatively regulates PREX1 transcript and protein levels. Using a Rac-GEF activation assay, we also showed that ΔNp63α reduces the levels of active PREX1. The inhibition of the PREX1-Rac1 signaling axis by ΔNp63α leads to impaired cell invasion, thus establishing the functional relevance of this link. Our results elucidated a novel molecular mechanism by which ΔNp63α negatively affects cancer cell invasion and identifies the ΔNp63α/Rac1 axis as a potential target for metastasis.
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Journal Article
ISSN	2058-7716
ISSN	2058-7716
DOI	10.1038/s41420-023-01789-0
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Article ; Online: Gi/o GPCRs drive the formation of actin-rich tunneling nanotubes in cancer cells via a Gβγ/PKCα/FARP1/Cdc42 axis.

Cooke, Mariana / Zhang, Suli / Cornejo Maciel, Fabiana / Kazanietz, Marcelo G

The Journal of biological chemistry

2023 Volume 299, Issue 8, Page(s) 104983

Abstract: The functional association between stimulation of G-protein-coupled receptors (GPCRs) by eicosanoids and actin cytoskeleton reorganization remains largely unexplored. Using a model of human adrenocortical cancer cells, here we established that activation ...

Abstract	The functional association between stimulation of G-protein-coupled receptors (GPCRs) by eicosanoids and actin cytoskeleton reorganization remains largely unexplored. Using a model of human adrenocortical cancer cells, here we established that activation of the GPCR OXER1 by its natural agonist, the eicosanoid 5-oxo-eicosatetraenoic acid, leads to the formation of filopodia-like elongated projections connecting adjacent cells, known as tunneling nanotube (TNT)-like structures. This effect is reduced by pertussis toxin and GUE1654, a biased antagonist for the Gβγ pathway downstream of OXER1 activation. We also observed pertussis toxin-dependent TNT biogenesis in response to lysophosphatidic acid, indicative of a general response driven by Gi/o-coupled GPCRs. TNT generation by either 5-oxo-eicosatetraenoic acid or lysophosphatidic acid is partially dependent on the transactivation of the epidermal growth factor receptor and impaired by phosphoinositide 3-kinase inhibition. Subsequent signaling analysis reveals a strict requirement of phospholipase C β3 and its downstream effector protein kinase Cα. Consistent with the established role of Rho small GTPases in the formation of actin-rich projecting structures, we identified the phosphoinositide 3-kinase-regulated guanine nucleotide exchange factor FARP1 as a GPCR effector essential for TNT formation, acting via Cdc42. Altogether, our study pioneers a link between Gi/o-coupled GPCRs and TNT development and sheds light into the intricate signaling pathways governing the generation of specialized actin-rich elongated structures in response to bioactive signaling lipids.
MeSH term(s)	Humans ; Actins/metabolism ; Neoplasms/metabolism ; Pertussis Toxin/pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Kinase C-alpha/genetics ; Protein Kinase C-alpha/metabolism ; rho GTP-Binding Proteins/metabolism ; Rho Guanine Nucleotide Exchange Factors/metabolism ; Cell Membrane Structures/metabolism ; Nanotubes ; Receptors, Eicosanoid/antagonists & inhibitors ; Receptors, Eicosanoid/metabolism ; Cell Line, Tumor ; Arachidonic Acids/metabolism ; Arachidonic Acids/pharmacology ; Signal Transduction
Chemical Substances	Actins ; FARP1 protein, human ; Pertussis Toxin (EC 2.4.2.31) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein Kinase C-alpha (EC 2.7.11.13) ; rho GTP-Binding Proteins (EC 3.6.5.2) ; Rho Guanine Nucleotide Exchange Factors ; Tunneling Nanotubes ; OXER1 protein, human ; Receptors, Eicosanoid ; 5-oxo-eicosatetraenoic acid ; Arachidonic Acids
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104983
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Article ; Online: Nonredundant Rac-GEF control of actin cytoskeleton reorganization.

Kazanietz, Marcelo G / Cooke, Mariana / Garcia-Mata, Rafael

Trends in cell biology

2022 Volume 32, Issue 10, Page(s) 815–818

Abstract: Rac-GEFs operate in a nonredundant manner as downstream effectors of receptor tyrosine kinases to promote ruffle formation, indicative of unique modes of regulation and targeting. Current research is shedding light on the intricate signaling paradigms ... ...

Abstract	Rac-GEFs operate in a nonredundant manner as downstream effectors of receptor tyrosine kinases to promote ruffle formation, indicative of unique modes of regulation and targeting. Current research is shedding light on the intricate signaling paradigms shaping spatiotemporal activation of the small GTPase Rac during the generation of actin-rich membrane protrusions.
MeSH term(s)	Actin Cytoskeleton/metabolism ; Actins/metabolism ; Humans ; Signal Transduction
Chemical Substances	Actins
Language	English
Publishing date	2022-06-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	30122-x
ISSN	1879-3088 ; 0962-8924
ISSN (online)	1879-3088
ISSN	0962-8924
DOI	10.1016/j.tcb.2022.06.003
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Article: Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer.

Cooke, Mariana / Baker, Martin J / Kazanietz, Marcelo G

Frontiers in cell and developmental biology

2020 Volume 8, Page(s) 118

Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) representing ∼85% of new diagnoses. The disease is often detected in an advanced metastatic stage, with poor prognosis and clinical outcome. In ... ...

Abstract	Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) representing ∼85% of new diagnoses. The disease is often detected in an advanced metastatic stage, with poor prognosis and clinical outcome. In order to escape from the primary tumor, cancer cells acquire highly motile and invasive phenotypes that involve the dynamic reorganization of the actin cytoskeleton. These processes are tightly regulated by Rac1, a small G-protein that participates in the formation of actin-rich membrane protrusions required for cancer cell motility and for the secretion of extracellular matrix (ECM)-degrading proteases. In this perspective article we focus on the mechanisms leading to aberrant Rac1 signaling in NSCLC progression and metastasis, highlighting the role of Rac Guanine nucleotide Exchange Factors (GEFs). A plausible scenario is that specific Rac-GEFs activate discrete intracellular pools of Rac1, leading to unique functional responses in the context of specific oncogenic drivers, such as mutant EGFR or mutant KRAS. The identification of dysregulated Rac signaling regulators may serve to predict critical biomarkers for metastatic disease in lung cancer patients, ultimately aiding in refining patient prognosis and decision-making in the clinical setting.
Language	English
Publishing date	2020-02-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2020.00118
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Article ; Online: Rho GTPases and the emerging role of tunneling nanotubes in physiology and disease.

Zhang, Suli / Kazanietz, Marcelo G / Cooke, Mariana

American journal of physiology. Cell physiology

2020 Volume 319, Issue 5, Page(s) C877–C884

Abstract: Tunneling nanotubes (TNTs) emerged as important specialized actin-rich membrane protrusions for cell-to-cell communication. These structures allow the intercellular exchange of material, such as ions, soluble proteins, receptors, vesicles and organelles, ...

Abstract	Tunneling nanotubes (TNTs) emerged as important specialized actin-rich membrane protrusions for cell-to-cell communication. These structures allow the intercellular exchange of material, such as ions, soluble proteins, receptors, vesicles and organelles, therefore exerting critical roles in normal cell function. Indeed, TNTs participate in a number of physiological processes, including embryogenesis, immune response, and osteoclastogenesis. TNTs have been also shown to contribute to the transmission of retroviruses (e.g., human immunodeficiency virus-1, HIV-1) and coronaviruses. As with other membrane protrusions, the involvement of Rho GTPases in the formation of these elongated structures is undisputable, although the mechanisms involved are not yet fully elucidated. The tight control of Rho GTPase function by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) strongly suggests that localized control of these Rho regulators may contribute to TNT assembly and disassembly. Deciphering the intricacies of the complex signaling mechanisms leading to actin reorganization and TNT development would reveal important information about their involvement in normal cellular physiology as well as unveil potential targets for disease management.
MeSH term(s)	Betacoronavirus/physiology ; COVID-19 ; Cell Communication ; Coronavirus Infections/transmission ; HIV Infections/transmission ; Humans ; Nanotubes ; Pandemics ; Pneumonia, Viral/transmission ; SARS-CoV-2 ; rho GTP-Binding Proteins/genetics ; rho GTP-Binding Proteins/metabolism
Chemical Substances	rho GTP-Binding Proteins (EC 3.6.5.2)
Keywords	covid19
Language	English
Publishing date	2020-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00351.2020
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Article ; Online: Quantification of ruffle area and dynamics in live or fixed lung adenocarcinoma cells.

Kreider-Letterman, Gabriel / Cooke, Mariana / Goicoechea, Silvia M / Kazanietz, Marcelo G / Garcia-Mata, Rafael

STAR protocols

2022 Volume 3, Issue 2, Page(s) 101437

Abstract: Ruffles are actin-rich membrane protrusions implicated in actin reorganization and initiation of cell motility. Here, we describe methods for measuring and analyzing ruffle dynamics in live cells and average ruffle area per cell in fixed samples. The ... ...

Abstract	Ruffles are actin-rich membrane protrusions implicated in actin reorganization and initiation of cell motility. Here, we describe methods for measuring and analyzing ruffle dynamics in live cells and average ruffle area per cell in fixed samples. The specific steps described are for the analysis of A549 lung adenocarcinoma cells, but the protocol can be applied to other cell types. The protocol has applications for dissecting the signaling events linked to ruffling. For complete details on the use and execution of this protocol, please refer to Cooke et al. (2021).
MeSH term(s)	Actins/metabolism ; Adenocarcinoma of Lung/metabolism ; Cell Membrane Structures/metabolism ; Cell Movement ; Humans
Chemical Substances	Actins
Language	English
Publishing date	2022-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.101437
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