The EphB6 Receptor: Kinase-Dead but Very Much Alive DOI Open Access

Timothy G. Strozen,

Jessica C. Sharpe, Evelyn D. Harris

и другие.

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(15), С. 8211 - 8211

Опубликована: Июль 30, 2021

The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, greater appreciation for the role perform in expanding repertoire signals generated by signal transduction systems fostered more field. acts molecular switch that capable modulating output clusters. Although biological effects activity are well defined, mechanisms function remain enigmatic. In this review, we use comparative approach postulate how scaffold recruit adaptor proteins cluster regulated. We suggest evolutionary repurposing into kinase-independent mammals involved activation loop SH3 domain-binding site. addition, employs same SAM domain linker juxtamembrane allosteric regulatory used kinase-positive receptors regulate function. As result, although kinase-dead, remains strategically active component signaling.

Язык: Английский

Evolution and Functions of Plant U-Box Proteins: From Protein Quality Control to Signaling DOI
Jana Trenner, Jacqueline Monaghan, Bushra Saeed

и другие.

Annual Review of Plant Biology, Год журнала: 2022, Номер 73(1), С. 93 - 121

Опубликована: Фев. 28, 2022

Posttranslational modifications add complexity and diversity to cellular proteomes. One of the most prevalent across eukaryotes is ubiquitination, which orchestrated by E3 ubiquitin ligases. U-box-containing ligases have massively expanded in plant kingdom diversified into U-box proteins (PUBs). PUBs likely originated from two or three ancestral forms, fusing with diverse functional subdomains that resulted neofunctionalization. Their emergence diversification may reflect adaptations stress during evolution, reflecting changes needs proteomes maintain homeostasis. Through their close association protein kinases, they are physically linked cell signaling hubs activate feedback loops dynamically pairing E2-ubiquitin-conjugating enzymes generate distinct polymers themselves act as signals. Here, we complement current knowledgewith comparative genomics gain a deeper understanding PUB function, focusing on evolution structural key residues, well various roles cells.

Язык: Английский

Процитировано

48
The dead phosphatases society: a review of the emerging roles of pseudophosphatases DOI Creative Commons
Veronika Reiterer, Krzysztof Pawłowski, Guillaume Desrochers

и другие.

FEBS Journal, Год журнала: 2020, Номер 287(19), С. 4198 - 4220

Опубликована: Июнь 2, 2020

Phosphatases are a diverse family of enzymes, comprising at least 10 distinct protein folds. Like most other enzyme families, many have sequence variations that predict an impairment or loss catalytic activity classifying them as pseudophosphatases. Research on pseudoenzymes is emerging area interest, with new biological functions repurposed from catalytically active relatives. Here, we provide overview the pseudophosphatases identified to date in all major phosphatase families. We will highlight degeneration various motifs and discuss challenges associated experimental determination inactivity. also summarize role diseases future directions this field.

Язык: Английский

Процитировано

40
The Critical Role of TRIB2 in Cancer and Therapy Resistance DOI Open Access

Víctor Mayoral-Varo,

Lucía Jiménez, Wolfgang Link

и другие.

Cancers, Год журнала: 2021, Номер 13(11), С. 2701 - 2701

Опубликована: Май 30, 2021

The Tribbles pseudokinases family consists of TRIB1, TRIB2, TRIB3 and STK40 and, although evolutionarily conserved, they have distinctive characteristics. members are expressed in a context cell compartment-dependent manner. For example, TRIB1 TRIB2 potent oncogenic activities vertebrate cells. Since the identification proteins as modulators multiple signalling pathways, recent studies linked their expression with several pathologies, including cancer. act protein adaptors involved ubiquitin-proteasome degradation system, bridge gap between substrates E3 ligases. Between TRIB members, is most ancestral member family. homeostasis regulation C/EBPα, β-catenin TCF4. On other hand, interacts MAPKK, AKT NFkB proteins, survival, proliferation immune response. Here, we review characteristic features structure its role many cancer subtypes an emphasis on function therapy resistance melanoma, leukemia glioblastoma. strong evidence chemoresistance provides attractive opportunity for targeting TRIB2.

Язык: Английский

Процитировано

37
Kinase-targeting small-molecule inhibitors and emerging bifunctional molecules DOI

Georg L. Goebel,

Xiaqiu Qiu,

Peng Wu

и другие.

Trends in Pharmacological Sciences, Год журнала: 2022, Номер 43(10), С. 866 - 881

Опубликована: Май 16, 2022

Язык: Английский

Процитировано

28
Nucleotide Binding, Evolutionary Insights, and Interaction Partners of the Pseudokinase Unc-51-like Kinase 4 DOI Creative Commons
Franziska Preuß, Deep Chatterjee, Sebastian Mathea

и другие.

Structure, Год журнала: 2020, Номер 28(11), С. 1184 - 1196.e6

Опубликована: Авг. 18, 2020

Язык: Английский

Процитировано

28
Pan-Cancer Analysis of Human Kinome Gene Expression and Promoter DNA Methylation Identifies Dark Kinase Biomarkers in Multiple Cancers DOI Open Access
Siddesh Southekal, Nitish K. Mishra, Chittibabu Guda

и другие.

Cancers, Год журнала: 2021, Номер 13(6), С. 1189 - 1189

Опубликована: Март 10, 2021

Kinases are a group of intracellular signaling molecules that play critical roles in various biological processes. Even though kinases comprise one the most well-known therapeutic targets, many have been understudied and therefore warrant further investigation. DNA methylation is key epigenetic regulators modulate gene expression. In this study, human kinome’s expression patterns were analyzed using level-3 TCGA data for 32 cancers. Unsupervised clustering based on kinome revealed grouping cancers their organ level tissue type. We observed significant differences overall kinase levels (hyper- hypomethylation) between tumor adjacent normal samples from same tissue. Methylation quantitative trait loci (meQTL) analysis with corresponding methylated probes highly mostly negative association (~92%) within 1.5 kb transcription start site (TSS). Several (dark) (PKMYT1, PNCK, BRSK2, ERN2, STK31, STK32A, MAPK4) also identified role patient survival. This study leverages results multi-omics to identify potential markers prognostic diagnostic importance our understanding cancer.

Язык: Английский

Процитировано

23
KinOrtho: a method for mapping human kinase orthologs across the tree of life and illuminating understudied kinases DOI Creative Commons
Liang‐Chin Huang, Rahil Taujale, Nathan Gravel

и другие.

BMC Bioinformatics, Год журнала: 2021, Номер 22(1)

Опубликована: Сен. 18, 2021

Protein kinases are among the largest druggable family of signaling proteins, involved in various human diseases, including cancers and neurodegenerative disorders. Despite their clinical relevance, nearly 30% 545 protein remain highly understudied. Comparative genomics is a powerful approach for predicting investigating functions understudied kinases. However, an incomplete knowledge kinase orthologs across fully sequenced kinomes severely limits application comparative approaches illuminating Here, we introduce KinOrtho, query- graph-based orthology inference method that combines full-length domain-based to map one-to-one 17 thousand species.Using multiple metrics, show KinOrtho performed better than existing methods identifying evolutionarily divergent species eliminated potential false positives by flagging sequences without proper domain further evaluation. We demonstrate advantage using fusion events, highlighting case between serine/threonine TAOK1 metabolic PIK3C2A with high co-expression cells. also identify evolutionary fission events involving OBSCN domains, value approaches. Using KinOrtho-defined orthologs, Gene Ontology annotations, machine learning, propose putative biological several kinases, role TP53RK cell cycle checkpoint(s), involvement TSSK3 TSSK6 acrosomal vesicle localization, ULK4 pseudokinase neuronal development.In sum, presents novel query-based tool orthologous relationships thousands proteomes can be applied any interest. exploit here its well-curated kinome ortholog set serve as valuable resource framework extended protein-family

Язык: Английский

Процитировано

23
Protein kinase C: release from quarantine by mTORC2 DOI Creative Commons
Timothy R. Baffi, Alexandra C. Newton

Trends in Biochemical Sciences, Год журнала: 2022, Номер 47(6), С. 518 - 530

Опубликована: Март 28, 2022

Язык: Английский

Процитировано

16
Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession DOI Creative Commons

Yuanrong Liu,

Dandan Song,

Dong-Min Liang

и другие.

Cell Death Discovery, Год журнала: 2022, Номер 8(1)

Опубликована: Июль 5, 2022

Abstract PKM2 is an important regulator of the aerobic glycolysis that plays a vital role in cancer cell metabolic reprogramming. In general, Trib2 considered as “pseudokinase”, contributing to different kinds cancer. However, detailed roles TRIB2 regulating metabolism by remain unclear. This study demonstrated TRIB2, not has kinase activity directly phosphorylate at serine 37 cells. The elevated pSer37-PKM2 would subsequently promote dimers enter into nucleus and increase expression LDHA, GLUT1, PTBP1. then proliferation migration TRIB2- or PKM2-overexpressed cultures. glucose uptake lactate production increased, but ATP content decreased PKM2-treated Experiments −/− mice further supported could regulate PKM2. Thus, these results reveal new its mechanism may be related lung vitro vivo, suggesting promising therapeutic targets for therapy controlling metabolism.

Язык: Английский

Процитировано

15
Erythropoietin-producing hepatocellular receptor B6 is highly expressed in non-functioning pituitary neuroendocrine tumors and its expression correlates with tumor size DOI Creative Commons
Hadara Rubinfeld, Zvi R. Cohen,

Uzi Bendavid

и другие.

Molecular Biology Reports, Год журнала: 2024, Номер 51(1)

Опубликована: Фев. 11, 2024

Abstract Background Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins involved tissue organization, synaptic plasticity, vascular development and progression various diseases including cancer. The kinase member EphB6 is a pseudokinase which has not attracted an equivalent amount interest as its enzymatically-active counterparts. aim this study was to assess expression pituitary tumors. Methods Results Human normal pituitaries tumors were examined for mRNA using real-time PCR protein by immunohistochemistry Western blotting. highly expressed non-functioning neuroendocrine (NF-PitNETs) versus GH-secreting PitNETs. correlated with tumor size. Conclusions Our results suggest aberrant NF-PitNETs. Future studies warranted determine role significance NF-PitNETs tumorigenesis.

Язык: Английский

Процитировано

3