Cleaving for growth: threonine aspartase 1—a protease relevant for development and disease

Stauber, Roland H.; Hahlbrock, Angelina; Knauer, Shirley K.; Wünsch, Desirée

doi:10.1096/fj.15-270611

Cited by 10 publications

(10 citation statements)

References 72 publications

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“…Proteolysis is an essential process in biology with roles as diverse as protein turnover, signaling regulation, and ECM modification; moreover, it is also the basis of various pathologies including cancer. One of the highly conserved proteases Threonine Aspartase 1 (Taspase 1) is overexpressed in multiple cancer conditions (Stauber et al, 2016). As current knowledge regarding the substrate specificity and regulatory mechanism of Taspase 1 is limited, CVM cell migration can potentially serve as a valuable model system to study this gene.…”

Section: Resultsmentioning

confidence: 99%

Comparative analysis of gene expression profiles for several migrating cell types identifies cell migration regulators

Bae

Macabenta

Curtis

et al. 2017

Mechanisms of Development

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Cell migration is an instrumental process that ensures cells are properly positioned to support the specification of distinct tissue types during development. To provide insight, we used fluorescence activated cell sorting (FACS) to isolate two migrating cell types from the Drosophila embryo: caudal visceral mesoderm (CVM) cells, precursors of longitudinal muscles of the gut, and hemocytes (HCs), the Drosophila equivalent of blood cells. ~350 genes were identified from each of the sorted samples using RNA-seq, and in situ hybridization was used to confirm expression within each cell type or, alternatively, within other interacting, co-sorted cell types. To start, the two gene expression profiling datasets were compared to identify cell migration regulators that are potentially generally-acting. 73 genes were present in both CVM cell and HC gene expression profiles, including the transcription factor Zinc finger homeodomain-1 (Zfh1). Comparisons with gene expression profiles of Drosophila border cells that migrate during oogenesis had a more limited overlap, with only the genes neyo (neo) and singed (sn) found to be expressed in border cells as well as CVM cells and HCs, respectively. neo encodes a protein with Zona pellucida domain linked to cell polarity, while sn encodes an actin binding protein. Tissue specific RNAi expression coupled with live in vivo imaging was used to confirm cell-autonomous roles for Zfh1 and Neo in supporting CVM cell migration, whereas previous studies had demonstrated a role for Sn in supporting HC migration. In addition, comparisons were made to migrating cells from vertebrates. Seven genes were found expressed by chick neural crest cells, CVM cells, and HCs including extracellular matrix (ECM) proteins and proteases. In summary, we show that genes shared in common between CVM cells, HCs, and other migrating cell types can help identify regulators of cell migration. Our analyses show that Neo in addition to Zfh1 and Sn studied previously impact cell migration. This study also suggests that modification of the extracellular milieu may be a fundamental requirement for cells that undergo cell streaming migratory behaviors.

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Section: Resultsmentioning

confidence: 99%

Comparative analysis of gene expression profiles for several migrating cell types identifies cell migration regulators

Bae

Macabenta

Curtis

et al. 2017

Mechanisms of Development

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“…Taspase is a conserved threonine-aspartic acid protease that cleaves mammalian and Drosophila MLL1/trithorax, as well as other nuclear proteins ( e.g. , TFIIA) associated with chromatin and transcription; mutations in human Taspase1 have been associated with certain forms of cancer, particularly those of the head and neck ( Hsieh et al 2003a ; Hsieh et al 2003b ; Khan et al 2005 ; Takeda et al 2006 ; Zhou et al 2006 ; Oyama et al 2013 ; Niizuma et al 2015 ; Takeda et al 2015 ; Stauber et al 2016 ; Gribko et al 2017 ). The four independent mutations are placed on the tasp-1 genomic locus as shown in Figure 5A .…”

Section: Resultsmentioning

confidence: 99%

A Strategy To Isolate Modifiers ofCaenorhabditis elegansLethal Mutations: Investigating the Endoderm Specifying Ability of the Intestinal Differentiation GATA Factor ELT-2

Wiesenfahrt

Duanmu

Snider

et al. 2018

G3 Genes|Genomes|Genetics

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The ELT-2 GATA factor normally functions in differentiation of the C. elegans endoderm, downstream of endoderm specification. We have previously shown that, if ELT-2 is expressed sufficiently early, it is also able to specify the endoderm and to replace all other members of the core GATA-factor transcriptional cascade (END-1, END-3, ELT-7). However, such rescue requires multiple copies (and presumably overexpression) of the end-1p::elt-2 cDNA transgene; a single copy of the transgene does not rescue. We have made this observation the basis of a genetic screen to search for genetic modifiers that allow a single copy of the end-1p::elt-2 cDNA transgene to rescue the lethality of the end-1end-3 double mutant. We performed this screen on a strain that has a single copy insertion of the transgene in an end-1end-3 background. These animals are kept alive by virtue of an extrachromosomal array containing multiple copies of the rescuing transgene; the extrachromosomal array also contains a toxin under heat shock control to counterselect for mutagenized survivors that have been able to lose the rescuing array. A screen of ∼14,000 mutagenized haploid genomes produced 17 independent surviving strains. Whole genome sequencing was performed to identify genes that incurred independent mutations in more than one surviving strain. The C. elegans gene tasp-1 was mutated in four independent strains. tasp-1 encodes the C. elegans homolog of Taspase, a threonine-aspartic acid protease that has been found, in both mammals and insects, to cleave several proteins involved in transcription, in particular MLL1/trithorax and TFIIA. A second gene, pqn-82, was mutated in two independent strains and encodes a glutamine-asparagine rich protein. tasp-1 and pqn-82 were verified as loss-of-function modifiers of the end-1p::elt-2 transgene by RNAi and by CRISPR/Cas9-induced mutations. In both cases, gene loss leads to modest increases in the level of ELT-2 protein in the early endoderm although ELT-2 levels do not strictly correlate with rescue. We suggest that tasp-1 and pqn-82 represent a class of genes acting in the early embryo to modulate levels of critical transcription factors or to modulate the responsiveness of critical target genes. The screen’s design, rescuing lethality with an extrachromosomal transgene followed by counterselection, has a background survival rate of <10−4 without mutagenesis and should be readily adapted to the general problem of identifying suppressors of C. elegans lethal mutations.

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“…Focusing on disease-relevant signalling-pathways in head and neck cancer, the Taspase1-TFIIA-CDKN2A axis is an interesting and potentially druggable target for HNSCC. In the past it could be demonstrated that Taspase1 uses different strategies to regulate biological processes like proliferation, cell cycle, differentiation and apoptosis 11 , 19 . Interestingly, our data support the hypothesis that Taspase1 fine-tunes the transcriptional activity of TFIIA via its subcellular localization and proteolytic cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the exclusively cis -active type 2 asparaginases, only Taspase1 is able to cleave distinct substrates in trans by hydrolyzing its target proteins at conserved (Q 3 [FILV] 2 D 1 ↓G 1′ x 2′ D 3′ D 4′ ) sites 14 , 15 . During mammalian development, Taspase1 plays an important role in the regulation of correct segmental identities, head morphogenesis and spermatogenesis 16 – 19 . However, the molecular mechanisms how Taspase1 may affect substrate functions through site-specific proteolysis still remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

Disease-relevant signalling-pathways in head and neck cancer: Taspase1’s proteolytic activity fine-tunes TFIIA function

Gribko

Hahlbrock

Strieth

et al. 2017

Sci Rep

Self Cite

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Head and neck cancer (HNC) is the seventh most common malignancy in the world and its prevailing form, the head and neck squamous cell carcinoma (HNSCC), is characterized as aggressive and invasive cancer type. The transcription factor II A (TFIIA), initially described as general regulator of RNA polymerase II-dependent transcription, is part of complex transcriptional networks also controlling mammalian head morphogenesis. Posttranslational cleavage of the TFIIA precursor by the oncologically relevant protease Taspase1 is crucial in this process. In contrast, the relevance of Taspase1-mediated TFIIA cleavage during oncogenesis of HNSCC is not characterized yet. Here, we performed genome-wide expression profiling of HNSCC which revealed significant downregulation of the TFIIA downstream target CDKN2A. To identify potential regulatory mechanisms of TFIIA on cellular level, we characterized nuclear-cytoplasmic transport and Taspase1-mediated cleavage of TFIIA variants. Unexpectedly, we identified an evolutionary conserved nuclear export signal (NES) counteracting nuclear localization and thus, transcriptional activity of TFIIA. Notably, proteolytic processing of TFIIA by Taspase1 was found to mask the NES, thereby promoting nuclear localization and transcriptional activation of TFIIA target genes, such as CDKN2A. Collectively, we here describe a hitherto unknown mechanism how cellular localization and Taspase1 cleavage fine-tunes transcriptional activity of TFIIA in HNSCC.

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Cleaving for growth: threonine aspartase 1—a protease relevant for development and disease

Abstract: From the beginning of life, proteases are

Cited by 10 publications

References 72 publications

Comparative analysis of gene expression profiles for several migrating cell types identifies cell migration regulators

Comparative analysis of gene expression profiles for several migrating cell types identifies cell migration regulators

A Strategy To Isolate Modifiers ofCaenorhabditis elegansLethal Mutations: Investigating the Endoderm Specifying Ability of the Intestinal Differentiation GATA Factor ELT-2

Disease-relevant signalling-pathways in head and neck cancer: Taspase1’s proteolytic activity fine-tunes TFIIA function

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