scholarly journals Essential role of CIB1 in regulating PAK1 activation and cell migration

2005 ◽  
Vol 170 (3) ◽  
pp. 465-476 ◽  
Author(s):  
Tina M. Leisner ◽  
Mingjuan Liu ◽  
Zahara M. Jaffer ◽  
Jonathan Chernoff ◽  
Leslie V. Parise
Keyword(s):  
Cell Migration ◽  
Specific Interaction ◽  
Dependent Manner ◽  
Lim Kinase ◽  
Calcium Dependent ◽  
Cellular Processes ◽  
Cofilin Phosphorylation ◽  
Pak1 Activation

p21-activated kinases (PAKs) regulate many cellular processes, including cytoskeletal rearrangement and cell migration. In this study, we report a direct and specific interaction of PAK1 with a 22-kD Ca2+-binding protein, CIB1, which results in PAK1 activation both in vitro and in vivo. CIB1 binds to PAK1 within discrete regions surrounding the inhibitory switch domain in a calcium-dependent manner, providing a potential mechanism of CIB1-induced PAK1 activation. CIB1 overexpression significantly decreases cell migration on fibronectin as a result of a PAK1-and LIM kinase–dependent increase in cofilin phosphorylation. Conversely, the RNA interference–mediated depletion of CIB1 increases cell migration and reduces normal adhesion-induced PAK1 activation and cofilin phosphorylation. Together, these results demonstrate that endogenous CIB1 is required for regulated adhesion-induced PAK1 activation and preferentially induces a PAK1-dependent pathway that can negatively regulate cell migration. These results point to CIB1 as a key regulator of PAK1 activation and signaling.

scholarly journals Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo

2013 ◽  
Vol 203 (4) ◽  
pp. 673-689 ◽  
Author(s):  
Ah-Lai Law ◽  
Anne Vehlow ◽  
Maria Kotini ◽  
Lauren Dodgson ◽  
Daniel Soong ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cell ◽  
Direct Interaction ◽  
Dependent Manner ◽  
Border Cell ◽  
Promote Cell Migration ◽  
Wave Complex

Cell migration is essential for development, but its deregulation causes metastasis. The Scar/WAVE complex is absolutely required for lamellipodia and is a key effector in cell migration, but its regulation in vivo is enigmatic. Lamellipodin (Lpd) controls lamellipodium formation through an unknown mechanism. Here, we report that Lpd directly binds active Rac, which regulates a direct interaction between Lpd and the Scar/WAVE complex via Abi. Consequently, Lpd controls lamellipodium size, cell migration speed, and persistence via Scar/WAVE in vitro. Moreover, Lpd knockout mice display defective pigmentation because fewer migrating neural crest-derived melanoblasts reach their target during development. Consistently, Lpd regulates mesenchymal neural crest cell migration cell autonomously in Xenopus laevis via the Scar/WAVE complex. Further, Lpd’s Drosophila melanogaster orthologue Pico binds Scar, and both regulate collective epithelial border cell migration. Pico also controls directed cell protrusions of border cell clusters in a Scar-dependent manner. Taken together, Lpd is an essential, evolutionary conserved regulator of the Scar/WAVE complex during cell migration in vivo.

Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321386
Author(s):  
Shushu Song ◽  
Yinghong Shi ◽  
Weicheng Wu ◽  
Hao Wu ◽  
Lei Chang ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Dependent Manner ◽  
Mice Model ◽  
Calcium Dependent ◽  
B Virus ◽  
P53 Activation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

ObjectiveDysfunction of endoplasmic reticulum (ER) proteins is closely related to homeostasis disturbance and malignant transformation of hepatocellular carcinoma (HCC). Reticulons (RTN) are a family of ER-resident proteins critical for maintaining ER function. Nevertheless, the precise roles of RTN in HCC remain largely unclear. The aim of the study is to examine the effect of reticulon family member RTN3 on HCC development and explore the underlying mechanisms.DesignClinical HCC samples were collected to assess the relationship between RTN3 expression and patients’ outcome. HCC cell lines were employed to examine the effects of RTN3 on cellular proliferation, apoptosis and signal transduction in vitro. Nude mice model was used to detect the role of RTN3 in modulating tumour growth in vivo.ResultsWe found that RTN3 was highly expressed in normal hepatocytes but frequently downregulated in HCC. Low RTN3 expression predicted poor outcome in patients with HCC in TP53 gene mutation and HBV infection status-dependent manner. RTN3 restrained HCC growth and induced apoptosis by activating p53. Mechanism studies indicated that RTN3 facilitated p53 Ser392 phosphorylation via Chk2 and enhanced subsequent p53 nuclear localisation. RTN3 interacted with Chk2, recruited it to ER and promoted its activation in an ER calcium-dependent manner. Nevertheless, the tumour suppressive effects of RTN3 were abrogated in HBV-positive cells. HBV surface antigen competed with Chk2 for RTN3 binding and blocked RTN3-mediated Chk2/p53 activation.ConclusionThe findings suggest that RTN3 functions as a novel suppressor of HCC by activating Chk2/p53 pathway and provide more clues to better understand the oncogenic effects of HBV.

scholarly journals Annexin VI: an intracellular target for ATP.

1999 ◽  
Vol 46 (3) ◽  
pp. 801-812 ◽  
Author(s):  
J Bandorowicz-Pikuła ◽  
M Danieluk ◽  
A Wrzosek ◽  
R Buś ◽  
R Buchet ◽  
...  
Keyword(s):  
Nucleotide Binding ◽  
Dependent Manner ◽  
Amino Acid Residues ◽  
Binding Motifs ◽  
Calcium Dependent ◽  
Annexin Vi ◽  
Self Association ◽  
Nucleotide Binding Proteins

Annexin VI (AnxVI), an Ca2+- and phospholipid-binding protein, interacts in vitro with ATP in a calcium-dependent manner. Experimental evidence indicates that its nucleotide-binding domain which is localized in the C-terminal half of the protein differs structurally from ATP/GTP-binding motifs found in other nucleotide-binding proteins. The amino-acid residues of AnxVI directly involved in ATP binding have not been yet defined. Binding of ATP to AnxVI induces changes in the secondary and tertiary structures of protein, affecting the affinity of AnxVI for Ca2+ and, in consequence, influencing the Ca2+-dependent activities of AnxVI: binding to F-actin and to membranous phospholipids, and self-association of the annexin molecules. These observations suggest that ATP is a functional ligand for AnxVI in vivo, and ATP-sensitive AnxVI may play the role of a factor coupling vesicular transport and calcium homeostasis to cellular metabolism.

SYK regulates B-cell migration by phosphorylation of the F-actin interacting protein SWAP-70

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1574-1584 ◽  
Author(s):  
Glen Pearce ◽  
Tatsiana Audzevich ◽  
Rolf Jessberger
Keyword(s):  
Cell Migration ◽  
B Cells ◽  
B Cell ◽  
Cell Polarization ◽  
Actin Binding ◽  
Lymphoid Tissues ◽  
Dependent Manner ◽  
Interacting Protein

Abstract B-cell migration into and within lymphoid tissues is not only central to the humoral immune response but also for the development of malignancies and autoimmunity. We previously demonstrated that SWAP-70, an F-actin-binding, Rho GTPase-interacting protein strongly expressed in activated B cells, is necessary for normal B-cell migration in vivo. SWAP-70 regulates integrin-mediated adhesion and cell attachment. Here we show that upon B-cell activation, SWAP-70 is extensively posttranslationally modified and becomes tyrosine phosphorylated by SYK at position 517. This phosphorylation inhibits binding of SWAP-70 to F-actin. Phospho-site mutants of SWAP-70 disrupt B-cell polarization in a dominant-negative fashion in vitro and impair migration in vivo. After CXCL12 stimulation of B cells SYK becomes activated and SWAP-70 is phosphorylated in a SYK-dependent manner. Use of the highly specific SYK inhibitor BAY61-3606 showed SYK activity is necessary for normal chemotaxis and B-cell polarization in vitro and for entry of B cells into lymph nodes in vivo. These findings demonstrate a novel requirement for SYK in migration and polarization of naive recirculating B cells and show that SWAP-70 is an important target of SYK in this pathway.

scholarly journals Collectin Kidney 1 Plays an Important Role in Innate Immunity against Streptococcus pneumoniae Infection

2017 ◽  
Vol 9 (2) ◽  
pp. 217-228 ◽  
Author(s):  
Insu Hwang ◽  
Kenichiro Mori ◽  
Katsuki Ohtani ◽  
Yasuyuki Matsuda ◽  
Nitai Roy ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Streptococcus Pneumoniae ◽  
Pulmonary Inflammation ◽  
Dependent Manner ◽  
Complement Pathway ◽  
Calcium Dependent ◽  
Host Protection ◽  
In The Wild

Collectins are C-type lectins that are involved in innate immunity as pattern recognition molecules. Recently, collectin kidney 1 (CL-K1) has been discovered, and in vitro studies have shown that CL-K1 binds to microbes and activates the lectin complement pathway. However, in vivo functions of CL-K1 against microbes have not been elucidated. To investigate the biological functions of CL-K1, we generated CL-K1 knockout (CL-K1-/-) mice and then performed a Streptococcus pneumoniae infection analysis. First, we found that recombinant human CL-K1 bound to S. pneumoniae in a calcium-dependent manner, and induced complement activation. CL-K1-/- mice sera formed less C3 deposition on S. pneumoniae. Furthermore, immunofluorescence analysis in the wild-type (WT) mice demonstrated that CL-K1 and C3 were localized on S. pneumoniae in infected lungs. CL-K1-/- mice revealed decreased phagocytosis of S. pneumoniae. Consequently, less S. pneumoniae clearance was observed in their lungs. CL-K1-/- mice showed severe pulmonary inflammation and weight loss in comparison with WT mice. Finally, the decreased clearance and severe pulmonary inflammation caused by S. pneumoniae infection might cause higher CL-K1-/- mice lethality. Our results suggest that CL-K1 might play an important role in host protection against S. pneumoniae infection through the activation of the lectin complement pathway.

scholarly journals NSun2 promotes cell migration through methylating autotaxin mRNA

2020 ◽  
Vol 295 (52) ◽  
pp. 18134-18147
Author(s):  
Xin Xu ◽  
Yihua Zhang ◽  
Junjie Zhang ◽  
Xiaotian Zhang
Keyword(s):  
Cell Migration ◽  
Biological Effects ◽  
Mrna Translation ◽  
Glioma Cell Line ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Protein Levels ◽  
Key Factor

NSun2 is an RNA methyltransferase introducing 5-methylcytosine into tRNAs, mRNAs, and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, whereas overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3′-UTR of ATX mRNA at cytosine 2756 in vitro and in vivo. Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated 5-methylcytosine methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.

scholarly journals Rab5 Mediates Caspase-8–promoted Cell Motility and Metastasis

2010 ◽  
Vol 21 (2) ◽  
pp. 369-376 ◽  
Author(s):  
Vicente A. Torres ◽  
Ainhoa Mielgo ◽  
Simone Barbero ◽  
Ruth Hsiao ◽  
John A. Wilkins ◽  
...  
Keyword(s):  
Cell Migration ◽  
Focal Adhesions ◽  
Caspase 8 ◽  
Environmental Cues ◽  
Dependent Manner ◽  
Cell Responses ◽  
Β1 Integrins ◽  
And Migration

Caspase-8 is a key apical sensory protein that governs cell responses to environmental cues, alternatively promoting apoptosis, proliferation, and cell migration. The proteins responsible for integration of these pathways, however, have remained elusive. Here, we reveal that Rab5 regulates caspase-8–dependent signaling from integrins. Integrin ligation leads to Rab5 activation, association with integrins, and activation of Rac, in a caspase-8–dependent manner. Rab5 activation promotes colocalization and coprecipitation of integrins with caspase-8, concomitant with Rab5 recruitment to integrin-rich regions such as focal adhesions and membrane ruffles. Moreover, caspase-8 expression promotes Rab5-mediated internalization and the recycling of β1 integrins, increasing cell migration independently of caspase catalytic activity. Conversely, Rab5 knockdown prevented caspase-8–mediated integrin signaling for Rac activation, cell migration, and apoptotic signaling, respectively. Similarly, Rab5 was critical for caspase-8–driven cell migration in vivo, because knockdown of Rab5 compromised the ability of caspase-8 to promote metastasis under nonapoptotic conditions. These studies identify Rab5 as a key integrator of caspase-8–mediated signal transduction downstream of integrins, regulating cell survival and migration in vivo and in vitro.

Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration

2012 ◽  
Vol 441 (3) ◽  
pp. 979-987 ◽  
Author(s):  
Ning Xiao ◽  
Hui Li ◽  
Jian Luo ◽  
Rui Wang ◽  
Haiquan Chen ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cell ◽  
Signalling Pathway ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Cancer Cell Migration ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

TRAF [TNF (tumour necrosis factor)-receptor-associated factor] 2 and 6 are essential adaptor proteins for the NF-κB (nuclear factor κB) signalling pathway, which play important roles in inflammation and immune response. Polyubiquitination of TRAF2 and TRAF6 is critical to their activities and functions in TNFα- and IL (interleukin)-1β-induced NF-κB activation. However, the regulation of TRAF2 and TRAF6 by deubiquitination remains incompletely understood. In the present study, we identified USP (ubiquitin-specific protease) 4 as a novel deubiquitinase targeting TRAF2 and TRAF6 for deubiquitination. We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3. Moreover, USP4 associates with TRAF6 both in vitro and in vivo, independent of its deubiquitinase activity. The USP domain is responsible for USP4 to interact with TRAF6. Ectopic expression of USP4 inhibits the TRAF2- and TRAF6-stimulated NF-κB reporter gene and negatively regulates the TNFα-induced IκBα (inhibitor of NF-κBα) degradation and NF-κB activation. Knockdown of USP4 significantly increased TNFα-induced cytokine expression. Furthermore, we found that USP4 deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro in a deubiquitinase activity-dependent manner. Importantly, the results of the present study showed that USP4 is a negative regulator of TNFα- and IL-1β-induced cancer cell migration. Taken together, the present study provides a novel insight into the regulation of the NF-κB signalling pathway and uncovers a previously unknown function of USP4 in cancer.

scholarly journals IQD proteins integrate auxin and calcium signaling to regulate microtubule dynamics during Arabidopsis development

2018 ◽  
Author(s):  
Jos R. Wendrich ◽  
Bao-Jun Yang ◽  
Pieter Mijnhout ◽  
Hong-Wei Xue ◽  
Bert De Rybel ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Binding Proteins ◽  
Preprophase Band ◽  
Auxin Signaling ◽  
Dependent Manner ◽  
Regulatory Pathways ◽  
Calcium Dependent ◽  
Specific Effects

AbstractGeometry and growth and division direction of individual cells are major contributors to plant organ shape and these processes are dependent on dynamics of microtubules (MT). Different MT structures, like the cortical microtubules, preprophase band and mitotic spindle, are characterized by diverse architectural dynamics (Hashimoto, 2015). While several MT binding proteins have been identified that have various effects on MT stability and architecture, they do not discriminate between the different MT structures. It is therefore likely that specific MT binding proteins exist that differentiate between MT structures in order to allow for the differences in architectural dynamics. Although evidence for the effect of specific cues, such as light and auxin, on MT dynamics has been shown in recent years (Lindeboom et al., 2013; Chen et al., 2014), it remains unknown how such cues are integrated and lead to specific effects. Here we provide evidence for how auxin and calcium signaling can be integrated to modulate MT dynamics, by means of IQD proteins. We show that the Arabidopsis IQD15-18 subclade of this family is regulated by auxin signaling, can bind calmodulins in a calcium-dependent manner and are evolutionarily conserved. Furthermore, AtIQD15-18 directly bind SPIRAL2 protein in vitro and in vivo and modulate its function, likely in a calmodulin-dependent way, thereby providing a missing link between two important regulatory pathways of MT dynamics.One sentence summaryIQD proteins integrate auxin and calcium signaling, two major signaling pathways, to control the cytoskeleton dynamics and cell shape of Arabidopsis.

scholarly journals Copine A Interacts with Actin Filaments and Plays a Role in Chemotaxis and Adhesion

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 758 ◽  
Author(s):  
Matthew J. Buccilli ◽  
April N. Ilacqua ◽  
Mingxi Han ◽  
Andrew A. Banas ◽  
Elise M. Wight ◽  
...  
Keyword(s):  
Protein Function ◽  
Actin Filaments ◽  
Model Organism ◽  
Dependent Manner ◽  
Developmental Defects ◽  
Calcium Dependent ◽  
Cellular Processes ◽  
Eukaryotic Organisms ◽  
Von Willebrand

Copines make up a family of calcium-dependent, phospholipid-binding proteins found in numerous eukaryotic organisms. Copine proteins consist of two C2 domains at the N-terminus followed by an A domain similar to the von Willebrand A domain found in integrins. We are studying copine protein function in the model organism, Dictyostelium discoideum, which has six copine genes, cpnA-cpnF. Previous research showed that cells lacking the cpnA gene exhibited a cytokinesis defect, a contractile vacuole defect, and developmental defects. To provide insight into the role of CpnA in these cellular processes, we used column chromatography and immunoprecipitation to isolate proteins that bind to CpnA. These proteins were identified by mass spectrometry. One of the proteins identified was actin. Purified CpnA was shown to bind to actin filaments in a calcium-dependent manner in vitro. cpnA− cells exhibited defects in three actin-based processes: chemotaxis, cell polarity, and adhesion. These results suggest that CpnA plays a role in chemotaxis and adhesion and may do so by interacting with actin filaments.

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