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Article ; Online: PP2A-B55alpha controls keratinocyte adhesion through dephosphorylation of the Desmoplakin C-terminus.

Perl, Abbey L / Koetsier, Jennifer L / Green, Kathleen J

2023 Volume 13, Issue 1, Page(s) 12720

Abstract: Critical for the maintenance of epidermal integrity and function are attachments between intermediate filaments (IF) and intercellular junctions called desmosomes. The desmosomal cytoplasmic plaque protein desmoplakin (DP) is essential for anchoring IF ... ...

Abstract	Critical for the maintenance of epidermal integrity and function are attachments between intermediate filaments (IF) and intercellular junctions called desmosomes. The desmosomal cytoplasmic plaque protein desmoplakin (DP) is essential for anchoring IF to the junction. DP-IF interactions are regulated by a phospho-regulatory motif within the DP C-terminus controlling keratinocyte intercellular adhesion. Here we identify the protein phosphatase 2A (PP2A)-B55α holoenzyme as the major serine/threonine phosphatase regulating DP's C-terminus and consequent intercellular adhesion. Using a combination of chemical and genetic approaches, we show that the PP2A-B55α holoenzyme interacts with DP at intercellular membranes in 2D- and 3D- epidermal models and human skin samples. Our experiments demonstrate that PP2A-B55α regulates the phosphorylation status of junctional DP and is required for maintaining strong desmosome-mediated intercellular adhesion. These data identify PP2A-B55α as part of a regulatory module capable of tuning intercellular adhesion strength and a candidate disease target in desmosome-related disorders of the skin and heart.
MeSH term(s)	Humans ; Desmoplakins ; Holoenzymes/metabolism ; Intercellular Junctions/metabolism ; Keratinocytes/metabolism ; Protein Phosphatase 2/metabolism
Chemical Substances	Desmoplakins ; Holoenzymes ; Protein Phosphatase 2 (EC 3.1.3.16) ; PPP2R2A protein, human
Language	English
Publishing date	2023-08-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-37874-8
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Article ; Online: Desmosomal Cadherins in Health and Disease.

Hegazy, Marihan / Perl, Abbey L / Svoboda, Sophia A / Green, Kathleen J

Annual review of pathology

2021 Volume 17, Page(s) 47–72

Abstract: Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmocollins, are related to the ... ...

Abstract	Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmocollins, are related to the classical cadherins, but their cytoplasmic domains are tailored for anchoring intermediate filaments instead of actin to sites of cell-cell adhesion. The resulting junctions are critical for resisting mechanical stress in tissues such as the skin and heart. Desmosomal cadherins also act as signaling hubs that promote differentiation and facilitate morphogenesis, creating more complex and effective tissue barriers in vertebrate tissues. Interference with desmosomal cadherin adhesive and supra-adhesive functions leads to a variety of autoimmune, hereditary, toxin-mediated, and malignant diseases. We review our current understanding of how desmosomal cadherins contribute to human health and disease, highlight gaps in our knowledge about their regulation and function, and introduce promising new directions toward combatting desmosome-related diseases.
MeSH term(s)	Cadherins/physiology ; Cell Adhesion/physiology ; Desmocollins ; Desmosomes/physiology ; Humans ; Signal Transduction
Chemical Substances	Cadherins ; Desmocollins
Language	English
Publishing date	2021-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2227429-7
ISSN	1553-4014 ; 1553-4006
ISSN (online)	1553-4014
ISSN	1553-4006
DOI	10.1146/annurev-pathol-042320-092912
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Article ; Online: Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis.

Roth-Carter, Quinn R / Burks, Hope E / Ren, Ziyou / Koetsier, Jennifer L / Tsoi, Lam C / Harms, Paul W / Xing, Xianying / Kirma, Joseph / Harmon, Robert M / Godsel, Lisa M / Perl, Abbey L / Gudjonsson, Johann E / Green, Kathleen J

JCI insight

2023 Volume 8, Issue 16

Abstract: Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. To better understand the ... ...

Abstract	Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. To better understand the underlying mechanisms leading to disease in these conditions, we performed RNA-seq on lesional skin samples from patients. The transcriptomic profiles of Darier, Hailey-Hailey, and Grover diseases were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases. Analysis of enriched pathways showed a shared increase in keratinocyte differentiation, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grover diseases. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in the acantholytic skin diseases. Furthermore, upstream regulator analysis suggested that a decrease in SRF/MRTF activity was responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared with normal skin. These findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grover diseases, and identify decreases in actin organization pathways as a unique signature present in these conditions.
MeSH term(s)	Humans ; Actins ; Skin/pathology ; Acantholysis/genetics ; Acantholysis/metabolism ; Skin Diseases/complications ; Skin Diseases/pathology
Chemical Substances	Actins
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.168955
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Article ; Online: Protein phosphatase 2A controls ongoing DNA replication by binding to and regulating cell division cycle 45 (CDC45).

Perl, Abbey L / O'Connor, Caitlin M / Fa, Pengyan / Mayca Pozo, Franklin / Zhang, Junran / Zhang, Youwei / Narla, Goutham

The Journal of biological chemistry

2019 Volume 294, Issue 45, Page(s) 17043–17059

Abstract: Genomic replication is a highly regulated process and represents both a potential benefit and liability to rapidly dividing cells; however, the precise post-translational mechanisms regulating genomic replication are incompletely understood. Protein ... ...

Abstract	Genomic replication is a highly regulated process and represents both a potential benefit and liability to rapidly dividing cells; however, the precise post-translational mechanisms regulating genomic replication are incompletely understood. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that regulates a diverse array of cellular processes. Here, utilizing both a gain-of-function chemical biology approach and loss-of-function genetic approaches to modulate PP2A activity, we found that PP2A regulates DNA replication. We demonstrate that increased PP2A activity can interrupt ongoing DNA replication, resulting in a prolonged S phase. The impaired replication resulted in a collapse of replication forks, inducing dsDNA breaks, homologous recombination, and a PP2A-dependent replication stress response. Additionally, we show that during replication, PP2A exists in complex with cell division cycle 45 (CDC45) and that increased PP2A activity caused dissociation of CDC45 and polymerase α from the replisome. Furthermore, we found that individuals harboring mutations in the PP2A Aα gene have a higher fraction of genomic alterations, suggesting that PP2A regulates ongoing replication as a mechanism for maintaining genomic integrity. These results reveal a new function for PP2A in regulating ongoing DNA replication and a potential role for PP2A in the intra-S-phase checkpoint.
MeSH term(s)	Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; DNA Damage ; DNA Replication ; Enzyme Activation ; Female ; Mice ; Protein Binding ; Protein Phosphatase 2/metabolism ; S Phase/genetics
Chemical Substances	CDC45 protein, human ; Cell Cycle Proteins ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2019-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.010432
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Article: Complete Genome of Bacillus subtilis Myophage Grass.

Miller, Stanton Y / Colquhoun, Jennifer M / Perl, Abbey L / Chamakura, Karthik R / Kuty Everett, Gabriel F

Genome announcements

2013 Volume 1, Issue 6

Abstract: Bacillus subtilis is a ubiquitous Gram-positive model organism. Here, we describe the complete genome of B. subtilus myophage Grass. Aside from genes encoding core proteins pertinent to the life cycle of the phage, Grass has several interesting features, ...

Abstract	Bacillus subtilis is a ubiquitous Gram-positive model organism. Here, we describe the complete genome of B. subtilus myophage Grass. Aside from genes encoding core proteins pertinent to the life cycle of the phage, Grass has several interesting features, including an FtsK/SpoIIIE protein.
Language	English
Publishing date	2013-12-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2704277-7
ISSN	2169-8287
ISSN	2169-8287
DOI	10.1128/genomeA.00857-13
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Article: Complete Genome of Bacillus subtilis Myophage CampHawk.

Ritz, Morgan P / Perl, Abbey L / Colquhoun, Jennifer M / Chamakura, Karthik R / Kuty Everett, Gabriel F

Genome announcements

2013 Volume 1, Issue 6

Abstract: The study of bacteriophages infecting the model organism Bacillus subtilis has provided an abundance of general knowledge and a platform for advances in biotechnology. Here, we announce the annotated genome of CampHawk, a B. subtilis phage. CampHawk was ... ...

Abstract	The study of bacteriophages infecting the model organism Bacillus subtilis has provided an abundance of general knowledge and a platform for advances in biotechnology. Here, we announce the annotated genome of CampHawk, a B. subtilis phage. CampHawk was found to be an SPO1-like phage with similar gene content and arrangement.
Language	English
Publishing date	2013-12-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2704277-7
ISSN	2169-8287
ISSN	2169-8287
DOI	10.1128/genomeA.00984-13
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Article: Complete Genome of Bacillus subtilis Myophage Grass

Miller, Stanton Y / Colquhoun, Jennifer M / Perl, Abbey L / Chamakura, Karthik R / Kuty Everett, Gabriel F

Genome announcements. 2013 Dec. 26, v. 1, no. 6

2013

Abstract	Bacillus subtilis is a ubiquitous Gram-positive model organism. Here, we describe the complete genome of B. subtilus myophage Grass. Aside from genes encoding core proteins pertinent to the life cycle of the phage, Grass has several interesting features, including an FtsK/SpoIIIE protein.
Keywords	Bacillus subtilis ; bacteriophages ; genes ; grasses ; proteins
Language	English
Dates of publication	2013-1226
Size	p. e00857-13.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	2704277-7
ISSN	2169-8287
ISSN	2169-8287
DOI	10.1128/genomeA.00857-13
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Article: Complete Genome of Bacillus subtilis Myophage CampHawk

Ritz, Morgan P / Perl, Abbey L / Colquhoun, Jennifer M / Chamakura, Karthik R / Kuty Everett, Gabriel F

Genome announcements. 2013 Dec. 26, v. 1, no. 6

2013

Abstract	The study of bacteriophages infecting the model organism Bacillus subtilis has provided an abundance of general knowledge and a platform for advances in biotechnology. Here, we announce the annotated genome of CampHawk, a B. subtilis phage. CampHawk was found to be an SPO1-like phage with similar gene content and arrangement.
Keywords	Bacillus subtilis ; bacteriophages ; biotechnology ; genes
Language	English
Dates of publication	2013-1226
Size	p. e00984-13.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	2704277-7
ISSN	2169-8287
ISSN	2169-8287
DOI	10.1128/genomeA.00984-13
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

Leonard, Daniel / Huang, Wei / Izadmehr, Sudeh / O'Connor, Caitlin M / Wiredja, Danica D / Wang, Zhizhi / Zaware, Nilesh / Chen, Yinghua / Schlatzer, Daniela M / Kiselar, Janna / Vasireddi, Nikhil / Schüchner, Stefan / Perl, Abbey L / Galsky, Matthew D / Xu, Wenqing / Brautigan, David L / Ogris, Egon / Taylor, Derek J / Narla, Goutham

Cell

2020 Volume 181, Issue 3, Page(s) 688–701.e16

Abstract: Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by ... ...

Abstract	Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Line, Tumor ; Enzyme Activators/metabolism ; HEK293 Cells ; Heterografts ; Humans ; Male ; Mice ; Mice, Nude ; Models, Molecular ; Multiprotein Complexes/metabolism ; Protein Phosphatase 2/chemistry ; Protein Phosphatase 2/metabolism ; Protein Subunits
Chemical Substances	Enzyme Activators ; Multiprotein Complexes ; PPP2R5A protein, human ; Protein Subunits ; Protein Phosphatase 2 (EC 3.1.3.16)
Language	English
Publishing date	2020-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.03.038
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Article ; Online: RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth.

Umesalma, Shaikamjad / Kaemmer, Courtney A / Kohlmeyer, Jordan L / Letney, Blake / Schab, Angela M / Reilly, Jacqueline A / Sheehy, Ryan M / Hagen, Jussara / Tiwari, Nitija / Zhan, Fenghuang / Leidinger, Mariah R / O'Dorisio, Thomas M / Dillon, Joseph / Merrill, Ronald A / Meyerholz, David K / Perl, Abbey L / Brown, Bart J / Braun, Terry A / Scott, Aaron T /

Ginader, Timothy / Taghiyev, Agshin F / Zamba, Gideon K / Howe, James R / Strack, Stefan / Bellizzi, Andrew M / Narla, Goutham / Darbro, Benjamin W / Quelle, Frederick W / Quelle, Dawn E

The Journal of clinical investigation

2019 Volume 129, Issue 4, Page(s) 1641–1653

Abstract: Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and ... ...

Abstract	Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.
MeSH term(s)	Carcinoma, Neuroendocrine/enzymology ; Carcinoma, Neuroendocrine/genetics ; Carcinoma, Neuroendocrine/pathology ; Cell Line, Tumor ; Enzyme Activators/pharmacology ; G1 Phase/drug effects ; G1 Phase/genetics ; Humans ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Pancreatic Neoplasms/enzymology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Protein Phosphatase 2/genetics ; Protein Phosphatase 2/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Enzyme Activators ; Oncogene Proteins ; Tumor Suppressor Proteins ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Protein Phosphatase 2 (EC 3.1.3.16) ; RABL6A protein, human (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2019-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI123049
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