Pseudophosphatases as Regulators of MAPK Signaling

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(22), С. 12595 - 12595

Опубликована: Ноя. 22, 2021

Mitogen-activated protein kinase (MAPK) signaling pathways are highly conserved regulators of eukaryotic cell function. These enzymes regulate many biological processes, including the cycle, apoptosis, differentiation, biosynthesis, and oncogenesis; therefore, tight control activity MAPK is critical. Kinases phosphatases well established as activators inhibitors, respectively. phosphorylate MAPKs, initiating controlling amplitude activation. In contrast, (MKPs) dephosphorylate downregulating duration signal. addition, within past decade, pseudoenzymes these two families, pseudokinases pseudophosphatases, have emerged bona fide regulators. This review discusses role pseudophosphatases in signaling, highlighting function phosphoserine/threonine/tyrosine-interacting (STYX) TAK1-binding (TAB 1) regulating MAPKs. Finally, a new paradigm considered for this well-studied cellular pathway, signal transduction general.

Язык: Английский

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Protein tyrosine phosphatases in cell adhesion

Biochemical Journal, Год журнала: 2021, Номер 478(5), С. 1061 - 1083

Опубликована: Март 10, 2021

Adhesive structures between cells and with the surrounding matrix are essential for development of multicellular organisms. In addition to providing mechanical integrity, they key signalling centres feedback on extracellular environment cell interior, vice versa. During development, mitosis repair, adhesions must undergo extensive remodelling. Post-translational modifications proteins within these complexes serve as switches activity. Tyrosine phosphorylation is an important modification in adhesion that dynamically regulated by protein tyrosine phosphatases (PTPs) kinases. Several PTPs implicated assembly maintenance adhesions, however, their functions remain poorly defined. The can act directly dephosphorylating adhesive complex components or function scaffolds. this review, we will focus human discuss individual roles major complexes, well Hippo signalling. We have collated PTP interactome adhesome datasets, which reveal connections relatively unexplored. Finally, reflect dysregulation disease.

Язык: Английский

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Emerging functions of pseudoenzymes

Biochemical Journal, Год журнала: 2023, Номер 480(10), С. 715 - 728

Опубликована: Май 19, 2023

As sequence and structural databases grow along with powerful analysis tools, the prevalence diversity of pseudoenzymes have become increasingly evident. Pseudoenzymes are present across tree life in a large number enzyme families. defined as proteins that lack conserved catalytic motifs based on analysis. However, some may migrated amino acids necessary for catalysis, allowing them to catalyze enzymatic reactions. Furthermore, retain several non-enzymatic functions such allosteric regulation, signal integration, scaffolding, competitive inhibition. In this review, we provide examples each mode action using pseudokinase, pseudophosphatase, pseudo ADP-ribosyltransferase We highlight methodologies facilitate biochemical functional characterization encourage further investigation burgeoning field.

Язык: Английский

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A PPP-type pseudophosphatase is required for the maintenance of basal complex integrity in Plasmodium falciparum

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 3, 2023

During its asexual blood stage, P. falciparum replicates via schizogony, wherein dozens of daughter cells are formed within a single parent. The basal complex, contractile ring that separates cells, is critical for schizogony. In this study, we identify Plasmodium complex protein essential maintenance. Using multiple microscopy techniques, demonstrate PfPPP8 required uniform expansion and maintenance integrity. We characterize as the founding member novel family pseudophosphatases with homologs in other Apicomplexan parasites. By co-immunoprecipitation, two additional new proteins. unique temporal localizations these proteins (late-arriving) (early-departing). work, protein, determine specific role segmentation, pseudophosphatase family, establish dynamic structure.

Язык: Английский

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The expanding landscape of canonical and non-canonical protein phosphorylation

Trends in Biochemical Sciences, Год журнала: 2024, Номер 49(11), С. 986 - 999

Опубликована: Сен. 11, 2024

Язык: Английский

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Release of CHK-2 from PPM-1.D anchorage schedules meiotic entry

Science Advances, Год журнала: 2022, Номер 8(7)

Опубликована: Фев. 16, 2022

Transition from the stem/progenitor cell fate to meiosis is mediated by several redundant posttranscriptional regulatory pathways in Caenorhabditis elegans . Interfering with all three branches causes tumorous germ lines. SCF PROM-1 comprises one branch and mediates a scheduled degradation step at entry into meiosis. prom-1 mutants show defects timely initiation of meiotic prophase I events, resulting high rates embryonic lethality. Here, we identify phosphatase PPM-1.D/Wip1 as crucial substrate for PROM-1. We report that PPM-1.D antagonizes CHK-2 kinase, key regulator initiation, including DNA double-strand breaks, chromosome pairing, synaptonemal complex formation. propose controls amount active via both catalytic noncatalytic activities; notably, regulation seems be entry. sequesters nuclear periphery, programmed –mediated liberates kinase promotes

Язык: Английский

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The Roles of Pseudophosphatases in Disease

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(13), С. 6924 - 6924

Опубликована: Июнь 28, 2021

The pseudophosphatases, atypical members of the protein tyrosine phosphatase family, have emerged as bona fide signaling regulators within past two decades. Their roles led to a renaissance pseudophosphatase and pseudoenyme fields, catapulting interest from mere curiosity intriguing relevant proteins investigate. Pseudophosphatases make up approximately fourteen percent are conserved throughout evolution. Pseudophosphatases, along with pseudokinases, important players in physiology pathophysiology. These kinase superfamily, respectively, rendered catalytically inactive through mutations their catalytic active signature motif and/or other domains required for catalysis. This new pursuit functions these has resulted an elucidation cascades diseases. There is rapid accumulation knowledge diseases linked dysregulation, such neuropathies various cancers. review analyzes involvement pseudophosphatases diseases, highlighting function role(s) pathologies, thus providing platform strongly consider them key therapeutic drug targets.

Язык: Английский

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Dual-specificity phosphatases 13 and 27 as key switches in muscle stem cell transition from proliferation to differentiation

Stem Cells, Год журнала: 2024, Номер 42(9), С. 830 - 847

Опубликована: Июль 8, 2024

Abstract Muscle regeneration depends on muscle stem cell (MuSC) activity. Myogenic regulatory factors, including myoblast determination protein 1 (MyoD), regulate the fate transition of MuSCs. However, direct target MYOD in process is not completely clear. Using previously established MyoD knock-in (MyoD-KI) mice, we revealed that targets dual-specificity phosphatase (Dusp) 13 and Dusp27. In Dusp13:Dusp27 double knock-out ability for after injury was reduced. Moreover, single-cell RNA sequencing MyoD-high expressing MuSCs from MyoD-KI mice Dusp13 Dusp27 are expressed only specific populations within MuSCs, which also express Myogenin. Overexpressing causes premature differentiation. Thus, propose a model where DUSP13 DUSP27 contribute to proliferation differentiation during myogenesis.

Язык: Английский

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HPV18 E7 inhibits LATS1 kinase and activates YAP1 by degrading PTPN14

mBio, Год журнала: 2024, Номер unknown

Опубликована: Сен. 9, 2024

ABSTRACT High-risk human papillomavirus (HPV) oncoproteins inactivate cellular tumor suppressors to reprogram host cell signaling pathways. HPV E7 proteins bind and degrade the suppressor PTPN14, thereby promoting nuclear localization of YAP1 oncoprotein inhibiting keratinocyte differentiation. is a transcriptional coactivator that drives epithelial stemness self-renewal. activity inhibited by highly conserved Hippo pathway, which frequently inactivated in cancers. MST1/2 LATS1/2 kinases form core kinase cascade. Active LATS1 phosphorylated on threonine 1079 inhibits phosphorylating it amino acids including serine 127. Here, we tested effect high-risk (carcinogenic) HPV18 pathway activity. We found either PTPN14 knockout or degradation decreased phosphorylation T1079 S127 keratinocytes Conversely, PTPN14-dependent differentiation required LATS certain PPxY motifs PTPN14. Neither nor putative phosphatase active sites were for promote Together, these data support inactivation reduce activity, IMPORTANCE The cascade YAP1, an driver There mounting evidence targeted viruses papillomavirus. promotes carcinogenic requires Blocking E7-dependent activation could inhibit HPV-mediated carcinogenesis, but mechanism activates has not been elucidated. Here report degrading kinase, reducing inhibitory YAP1. These can activate strengthen link between cells.

Язык: Английский

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Structural characterization of a pathogenic mutant of human protein tyrosine phosphatase PTPN2 ( Cys216Gly ) that causes very early onset autoimmune enteropathy

Protein Science, Год журнала: 2021, Номер 31(2), С. 538 - 544

Опубликована: Ноя. 22, 2021

PTPN2 is an important protein tyrosine phosphatase (PTP) that plays a key role in cell signaling. Deletions or inactivating mutations of have been described different pathologies and underline its critical hematopoiesis, autoimmunity, inflammation. Surprisingly, despite the major pathophysiological implications PTPN2, structural analysis this PTP notably pathogenic mutants remains poorly documented. Contrary to other human enzymes, date, only one structure (wild-type form) has reported. Here, we report first crystal mutant (Cys216Gly) causes autoimmune enteropathy. We show particular adopts classical fold. More importantly, albeit inactive, retains ability bind substrates adopt characteristic catalytically competent closed form enzymes. This novel may serve as new tool better understand structures impacts mutations. Moreover, C216G could also be helpful design specific ligands/inhibitors.

Язык: Английский

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