scholarly journals The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events

2019 ◽  
Author(s):  
Andrew J. Spracklen ◽  
Emma M. Thornton-Kolbe ◽  
Alison N. Bonner ◽  
Alexandru Florea ◽  
Peter J. Compton ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neuronal Development ◽  
Adapter Proteins ◽  
Mitotic Spindles ◽  
Fourth Chromosome ◽  
Oncogenic Signaling ◽  
Surface Receptors ◽  
Downstream Signaling ◽  
Cytoskeletal Dynamics ◽  
And Behavior

AbstractSmall SH2/SH3 adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The Crk family has tissue-specific roles in phagocytosis, cell migration and neuronal development, and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with shRNA and CRISPR technology to assess Crk’s function in Drosophila morphogenesis. We found Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates levels of the Arp2/3 complex, its regulator SCAR, and F-actin in actin caps and pseudocleavage furrows. Crk loss leads to loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.

scholarly journals The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events

2019 ◽  
Vol 30 (18) ◽  
pp. 2399-2421 ◽  
Author(s):  
Andrew J. Spracklen ◽  
Emma M. Thornton-Kolbe ◽  
Alison N. Bonner ◽  
Alexandru Florea ◽  
Peter J. Compton ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neuronal Development ◽  
Adapter Proteins ◽  
Filamentous Actin ◽  
Fourth Chromosome ◽  
Oncogenic Signaling ◽  
Surface Receptors ◽  
Downstream Signaling ◽  
Cytoskeletal Dynamics ◽  
Camp Receptor

Small Src homology domain 2 (SH2) and 3 (SH3) adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The CT10 regulator of kinase (Crk) family has tissue-specific roles in phagocytosis, cell migration, and neuronal development and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with short hairpin RNA and CRISPR technology to assess Crk’s function in Drosophila morphogenesis. We found that Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates cortical localization of the actin-related protein 2/3 complex (Arp2/3), its regulator suppressor of cAMP receptor (SCAR), and filamentous actin to actin caps and pseudocleavage furrows. Crk loss leads to the loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.

scholarly journals Phospholipase D: molecular and cell biology of a novel gene family

2000 ◽  
Vol 345 (3) ◽  
pp. 401-415 ◽  
Author(s):  
Mordechai LISCOVITCH ◽  
Malgorzata CZARNY ◽  
Giusy FIUCCI ◽  
Xiaoqing TANG
Keyword(s):  
Cell Fate ◽  
Phospholipase D ◽  
Cell Biology ◽  
Cell Function ◽  
Membrane Vesicle ◽  
Signal Molecules ◽  
Sequence Motifs ◽  
Surface Receptors ◽  
Extracellular Signal ◽  
Cytoskeletal Dynamics

Interaction of extracellular-signal molecules with cell-surface receptors often activates a phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine and other phospholipids, generating phosphatidic acid. The activation of PLD is believed to play an important role in the regulation of cell function and cell fate. Multiple PLD activities were characterized in eukaryotic cells, and, more recently, several PLD genes have been cloned. A PLD gene superfamily, defined by a number of structural domains and sequence motifs, also includes phosphatidyltransferases and certain phosphodiesterases. Among the eukaryotic PLD genes are those from mammals, nematodes, fungi and plants. The present review focuses on the structure, localization, regulation and possible functions of cloned mammalian and yeast PLDs. In addition, an overview of plant PLD genes, and of several distinct PLD activities that have not yet been cloned, is provided. Emerging evidence from recent work employing new molecular tools indicates that different PLD isoforms are localized in distinct cellular organelles, where they are likely to serve diverse functions in signal transduction, membrane vesicle trafficking and cytoskeletal dynamics.

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

2021 ◽  
Vol 80 (5) ◽  
pp. 467-475
Author(s):  
Yu-Qing Li ◽  
C Shun Wong
Keyword(s):  
Cell Fate ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Neuronal Development ◽  
Adenosine Monophosphate ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Wild Type ◽  
Newborn Neuron ◽  
Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

scholarly journals Cyto-friendly polymerization at cell surfaces modulates cell fate by clustering cell-surface receptors

2020 ◽  
Vol 11 (16) ◽  
pp. 4221-4225 ◽  
Author(s):  
Jing Qi ◽  
Weishuo Li ◽  
Xiaoling Xu ◽  
Feiyang Jin ◽  
Di Liu ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fate ◽  
Cell Surface Receptors ◽  
Cell Surfaces ◽  
Receptor Clustering ◽  
Surface Polymerization ◽  
Surface Receptors ◽  
Anti Cd20 ◽  
In Cells

Cell-surface polymerization of anti-CD20 aptamer modified macromer to induce CD20 receptor clustering, and effectively initiate the apoptotic signals in cells.

scholarly journals Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior

Stem Cells ◽  
2015 ◽  
Vol 33 (9) ◽  
pp. 2748-2761 ◽  
Author(s):  
Sylwia Bobis-Wozowicz ◽  
Katarzyna Kmiotek ◽  
Malgorzata Sekula ◽  
Sylwia Kedracka-Krok ◽  
Elzbieta Kamycka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Heart Cells ◽  
Induced Pluripotent ◽  
And Behavior ◽  
Fate And Behavior

scholarly journals Vav Family Proteins Couple to Diverse Cell Surface Receptors

2000 ◽  
Vol 20 (17) ◽  
pp. 6364-6373 ◽  
Author(s):  
Sheri L. Moores ◽  
Laura M. Selfors ◽  
Jessica Fredericks ◽  
Timo Breit ◽  
Keiko Fujikawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Receptor Activation ◽  
Cell Surface Receptors ◽  
Nucleotide Exchange ◽  
Surface Receptors ◽  
Downstream Signaling

ABSTRACT Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface receptors to downstream signaling proteins. Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3, which are broadly expressed, can couple with similar classes of receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3 at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and multiple phosphorylated tyrosine residues on the PDGF receptor were able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in nonhematopoietic cells unless the protein tyrosine kinase Syk was also expressed, suggesting that integrin activation of Vav proteins may be restricted to cell types that express particular tyrosine kinases. In addition, we found that Vav1, but not Vav2 or Vav3, can efficiently cooperate with T-cell receptor signaling to enhance NFAT-dependent transcription, while Vav1 and Vav3, but not Vav2, can enhance NFκB-dependent transcription. Thus, although each Vav isoform can respond to similar cell surface receptors, there are isoform-specific differences in their activation of downstream signaling pathways.

scholarly journals Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

2019 ◽  
Author(s):  
J. Martinez-Fabregas ◽  
S. Wilmes ◽  
L. Wang ◽  
M. Hafer ◽  
E. Pohler ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Ex Vivo ◽  
Treg Cells ◽  
Cytokine Receptor ◽  
Binding Kinetics ◽  
Functional Selectivity ◽  
Gene Expression Response ◽  
Surface Receptors ◽  
Downstream Signaling ◽  
Stat3 Phosphorylation

ABSTRACTCytokines activate downstream signaling networks via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered variants of IL-6 with different affinities to the gp130 receptor chain to investigate how cytokine receptor binding kinetics influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes, from minimal to full agonist, and induced biased signaling, with changes in receptor binding kinetics affecting more profoundly STAT1 than STAT3 phosphorylation. We show that this differential signaling arises from defective translocation of ligand-gp130 complexes to the endosomal compartment and competitive STAT1/STAT3 binding to phospho-tyrosines in gp130, and results in unique patterns of STAT3 binding to chromatin. This, in turn, leads to a graded gene expression response and substantial differences in ex vivo differentiation of Th17, Th1 and Treg cells. These results provide a molecular understanding of signaling biased by cytokine receptors, and demonstrate that manipulation of signaling thresholds is a useful strategy to decouple cytokine functional pleiotropy.

scholarly journals Glycans and glycosaminoglycans in neurobiology: key regulators of neuronal cell function and fate

2018 ◽  
Vol 475 (15) ◽  
pp. 2511-2545 ◽  
Author(s):  
Anthony J. Hayes ◽  
James Melrose
Keyword(s):  
Cell Fate ◽  
Information Transfer ◽  
Cell Function ◽  
Dermatan Sulfate ◽  
Neuronal Cell ◽  
Keratan Sulfate ◽  
Neural Function ◽  
Cellular Survival ◽  
Downstream Signaling ◽  
Blood Group Substances

The aim of the present study was to examine the roles of l-fucose and the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin sulfate/dermatan sulfate (CS/DS) with selected functional molecules in neural tissues. Cell surface glycans and GAGs have evolved over millions of years to become cellular mediators which regulate fundamental aspects of cellular survival. The glycocalyx, which surrounds all cells, actuates responses to growth factors, cytokines and morphogens at the cellular boundary, silencing or activating downstream signaling pathways and gene expression. In this review, we have focused on interactions mediated by l-fucose, KS and CS/DS in the central and peripheral nervous systems. Fucose makes critical contributions in the area of molecular recognition and information transfer in the blood group substances, cytotoxic immunoglobulins, cell fate-mediated Notch-1 interactions, regulation of selectin-mediated neutrophil extravasation in innate immunity and CD-34-mediated new blood vessel development, and the targeting of neuroprogenitor cells to damaged neural tissue. Fucosylated glycoproteins regulate delivery of synaptic neurotransmitters and neural function. Neural KS proteoglycans (PGs) were examined in terms of cellular regulation and their interactive properties with neuroregulatory molecules. The paradoxical properties of CS/DS isomers decorating matrix and transmembrane PGs and the positive and negative regulatory cues they provide to neurons are also discussed.

scholarly journals Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 987 ◽  
Author(s):  
Peter M.J. Quinn ◽  
Jan Wijnholds
Keyword(s):  
Stem Cell ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Cell Polarity ◽  
Apical Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Downstream Signaling ◽  
Fetal Retina ◽  
Crumbs Complex

The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation.

scholarly journals Cell shape and intercellular adhesion regulate mitotic spindle orientation

2019 ◽  
Vol 30 (19) ◽  
pp. 2458-2468 ◽  
Author(s):  
Jingchen Li ◽  
Longcan Cheng ◽  
Hongyuan Jiang
Keyword(s):  
Cell Division ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Cell Shape ◽  
Intercellular Adhesion ◽  
Shape Anisotropy ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
Strong Adhesion ◽  
Fate Decision

Cell division orientation plays an essential role in tissue morphogenesis and cell fate decision. Recent studies showed that either cell shape or adhesion geometry can regulate the orientation of mitotic spindles and thereby the cell division orientation. However, how they together regulate the spindle orientation remains largely unclear. In this work, we use a general computational model to investigate the competitive mechanism of determining the spindle orientation between cell shape and intercellular adhesion in epithelial cells. We find the spindle orientation is dominated by the intercellular adhesion when the cell shape anisotropy is small, but dominated by the cell shape when the shape anisotropy is large. A strong adhesion and moderate adhesive size can ensure the planar division of epithelial cells with large apico-basal elongation. We also find the spindle orientation could be perpendicular to the adhesive region when only one side of the cell is adhered to an E-cadherin–coated matrix. But after the cell is compressed, the spindle orientation is governed by the cell shape and the spindle will be parallel to the adhesive region when the cell shape anisotropy is large. Finally, we demonstrate the competition between cell shape and tricellular junctions can also effectively regulate the spindle orientation.

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