scholarly journals NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

2019 ◽  
Vol 11 (11) ◽  
pp. 994-1005 ◽  
Author(s):  
Ran Wei ◽  
Xuguang Liu ◽  
Courtney Voss ◽  
Wentao Qin ◽  
Lina Dagnino ◽  
...  
Keyword(s):  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Degradation Pathway ◽  
Anaplastic Lymphoma ◽  
Mechanistic Insight ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

scholarly journals Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1909
Author(s):  
Joachim T. Siaw ◽  
Jonatan L. Gabre ◽  
Ezgi Uçkun ◽  
Marc Vigny ◽  
Wancun Zhang ◽  
...  
Keyword(s):  
Genome Engineering ◽  
Neuroblastoma Cells ◽  
Gene Signature ◽  
Additional Insight ◽  
Downstream Target ◽  
Anaplastic Lymphoma ◽  
Extracellular Matrix Components ◽  
Transforming Gene ◽  
Insight Into

Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.

The Sox-domain containing geneDichaete/fish-hookacts in concert withvndandindto regulate cell fate in theDrosophilaneuroectoderm

Development ◽  
2002 ◽  
Vol 129 (5) ◽  
pp. 1165-1174 ◽  
Author(s):  
Guoyan Zhao ◽  
James B. Skeath
Keyword(s):  
Cell Fate ◽  
Nerve Cord ◽  
Double Mutant ◽  
Ventral Nerve Cord ◽  
Egf Receptor ◽  
Dorsoventral Axis ◽  
Mutant Analysis ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Important Regulator

In the Drosophila embryonic central nervous system, neural stem cells, called neuroblasts, acquire fates in a position-specific manner. Recent work has identified a set of genes that functions along the dorsoventral axis to enable neuroblasts that develop in different dorsoventral domains to acquire distinct fates. These genes include the evolutionarily conserved transcription factors ventral nerve cord defective and intermediate neuroblasts defective, as well as the Drosophila EGF receptor. We show that the Sox-domain-containing gene Dichaete/fish-hook also plays a crucial role to pattern the neuroectoderm along the DV axis. Dichaete is expressed in the medial and intermediate columns of the neuroectoderm, and mutant analysis indicates that Dichaete regulates cell fate and neuroblast formation in these domains. Molecular epistasis tests, double mutant analysis and dosage-sensitive interactions demonstrate that during these processes, Dichaete functions in parallel with ventral nerve cord defective and intermediate neuroblasts defective, and downstream of EGF receptor signaling to mediate its effect on development. These results identify Dichaete as an important regulator of dorsoventral pattern in the neuroectoderm, and indicate that Dichaete acts in concert with ventral nerve cord defective and intermediate neuroblasts defective to regulate pattern and cell fate in the neuroectoderm.

scholarly journals KH-type splicing regulatory protein is a new component of chromatoid body

Reproduction ◽  
2017 ◽  
Vol 154 (6) ◽  
pp. 723-733 ◽  
Author(s):  
Huijuan Zhang ◽  
Guishuan Wang ◽  
Lin Liu ◽  
Xiaolin Liang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Germ Cell ◽  
Knockout Mice ◽  
Binding Protein ◽  
Regulatory Protein ◽  
Somatic Cells ◽  
Chromatoid Body ◽  
Mechanistic Insight ◽  
Insight Into

The chromatoid body (CB) is a specific cloud-like structure in the cytoplasm of haploid spermatids. Recent findings indicate that CB is identified as a male germ cell-specific RNA storage and processing center, but its function has remained elusive for decades. In somatic cells, KH-type splicing regulatory protein (KSRP) is involved in regulating gene expression and maturation of select microRNAs (miRNAs). However, the function of KSRP in spermatogenesis remains unclear. In this study, we showed that KSRP partly localizes in CB, as a component of CB. KSRP interacts with proteins (mouse VASA homolog (MVH), polyadenylate-binding protein 1 (PABP1) and polyadenylate-binding protein 2 (PABP2)), mRNAs (Tnp2 and Odf1) and microRNAs (microRNA-182) in mouse CB. Moreover, KSRP may regulate the integrity of CB via DDX5-miRNA-182 pathway. In addition, we found abnormal expressions of CB component in testes of Ksrp-knockout mice and of patients with hypospermatogenesis. Thus, our results provide mechanistic insight into the role of KSRP in spermatogenesis.

Spalt modifies EGFR-mediated induction of chordotonal precursors in the embryonic PNS of Drosophila promoting the development of oenocytes

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 711-722 ◽  
Author(s):  
T.E. Rusten ◽  
R. Cantera ◽  
J. Urban ◽  
G. Technau ◽  
F.C. Kafatos ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Fate ◽  
System Development ◽  
Cell Types ◽  
Nervous System Development ◽  
Dual Function ◽  
Evolutionarily Conserved ◽  
A Cell ◽  
And Migration

Genes of the spalt family encode nuclear zinc finger proteins. In Drosophila melanogaster, they are necessary for the establishment of head/trunk identity, correct tracheal migration and patterning of the wing imaginal disc. Spalt proteins display a predominant pattern of expression in the nervous system, not only in Drosophila but also in species of fish, mouse, frog and human, suggesting an evolutionarily conserved role for these proteins in nervous system development. Here we show that Spalt works as a cell fate switch between two EGFR-induced cell types, the oenocytes and the precursors of the pentascolopodial organ in the embryonic peripheral nervous system. We show that removal of spalt increases the number of scolopodia, as a result of extra secondary recruitment of precursor cells at the expense of the oenocytes. In addition, the absence of spalt causes defects in the normal migration of the pentascolopodial organ. The dual function of spalt in the development of this organ, recruitment of precursors and migration, is reminiscent of its role in tracheal formation and of the role of a spalt homologue, sem-4, in the Caenorhabditis elegans nervous system.

Mechanistic insight into the role of metformin in Alzheimer's disease

Life Sciences ◽  
2022 ◽  
pp. 120299
Author(s):  
Mehdi Sanati ◽  
Samaneh Aminyavari ◽  
Amir R. Afshari ◽  
Amirhossein Sahebkar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mechanistic Insight ◽  
Insight Into

scholarly journals Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Suk Min Jang ◽  
Catherine Lachance ◽  
Wenyi Mi ◽  
Jie Lyu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Memory Impairment ◽  
Target Genes ◽  
Epigenetic Mark ◽  
Mechanistic Insight ◽  
Genomic Analyses ◽  
Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

scholarly journals The WT1-like transcription factor Klumpfuss maintains lineage commitment of enterocyte progenitors in the Drosophila intestine

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jerome Korzelius ◽  
Sina Azami ◽  
Tal Ronnen-Oron ◽  
Philipp Koch ◽  
Maik Baldauf ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Lineage Commitment ◽  
Proneural Gene ◽  
Cell Lineages ◽  
Daughter Cells ◽  
Mechanistic Insight ◽  
Insight Into

Abstract In adult epithelial stem cell lineages, the precise differentiation of daughter cells is critical to maintain tissue homeostasis. Notch signaling controls the choice between absorptive and entero-endocrine cell differentiation in both the mammalian small intestine and the Drosophila midgut, yet how Notch promotes lineage restriction remains unclear. Here, we describe a role for the transcription factor Klumpfuss (Klu) in restricting the fate of enteroblasts (EBs) in the Drosophila intestine. Klu is induced in Notch-positive EBs and its activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) fate by repressing the action of the proneural gene Scute, which is essential for EE differentiation. Loss of Klu results in differentiation of EBs into EE cells. Our findings provide mechanistic insight into how lineage commitment in progenitor cell differentiation can be ensured downstream of initial specification cues.

Mechanistic insight into the role of immunocastration on eliminating skatole in boars

2019 ◽  
Vol 131 ◽  
pp. 32-40 ◽  
Author(s):  
Xingfa Han ◽  
Min Zhou ◽  
Xiaohan Cao ◽  
Xiaogang Du ◽  
Fengyan Meng ◽  
...  
Keyword(s):  
Mechanistic Insight ◽  
Insight Into
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