scholarly journals VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology

2019 ◽  
Vol 30 (14) ◽  
pp. 1655-1663 ◽  
Author(s):  
HyeIn Jang ◽  
Eun Ryoung Jang ◽  
Patricia G. Wilson ◽  
Daniel Anderson ◽  
Emilia Galperin
Keyword(s):  
Atpase Activity ◽  
Frontotemporal Dementia ◽  
Inclusion Body ◽  
Critical Role ◽  
Germline Mutations ◽  
Aaa Atpase ◽  
Ubiquitin System ◽  
Signaling Axis ◽  
Mechanistic Basis

Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the stoichiometry of HUWE1 in the Shoc2 complex as well as HUWE1-mediated allosteric ubiquitination of the Shoc2 scaffold and the RAF-1 kinase. Abrogated ATPase activity leads to augmented ubiquitination of Shoc2/RAF-1 and altered phosphorylation of RAF-1. We found that in fibroblasts from patients with inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) that harbor germline mutations in VCP, the levels of Shoc2 ubiquitination and ERK1/2 phosphorylation are imbalanced. This study provides a mechanistic basis for the critical role of VCP in the regulation of the ERK1/2 pathway and reveals a previously unrecognized function of the ERK1/2 pathway in the pathogenesis of IBMPFD.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

scholarly journals O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Maria Cecilia Oliveira-Nunes ◽  
Glaucia Julião ◽  
Aline Menezes ◽  
Fernanda Mariath ◽  
John A. Hanover ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Critical Role ◽  
Molecular Signature ◽  
Label Free ◽  
Intercellular Signaling ◽  
Tumor Aggressiveness ◽  
Signaling Axis ◽  
Literature Evidence ◽  
Therapeutic Tools

AbstractGlioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critical role in maintaining the composition of the GBM secretome, whereas inhibition of OGA activity disrupts the intercellular signaling via microvesicles. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered by activity inhibition of O-GlcNAcase (iOGA). Among these proteins, we observed that proteins related to proteasome activity and to regulation of immune response in the tumor microenvironment were consistently downregulated in GBM cells upon iOGA. While the proteins IGFBP3, IL-6 and HSPA5 were downregulated in GBM iOGA cells, the protein SQSTM1/p62 was exclusively found in GBM cells under iOGA. These findings were in line with literature evidence on the role of p62/IL-6 signaling axis in suppressing tumor aggressiveness and our experimental evidence showing a decrease in radioresistance potential of these cells. Taken together, our findings provide evidence that OGA activity may regulate the p62 and IL-6 abundance in the GBM secretome. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.

scholarly journals SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology

2021 ◽  
Vol 22 (12) ◽  
pp. 6613
Author(s):  
Fernando C. Baltanás ◽  
Rósula García-Navas ◽  
Eugenio Santos
Keyword(s):  
Expression Patterns ◽  
Critical Role ◽  
Ras Signaling ◽  
Epidermal Stem Cell ◽  
Functional Specificity ◽  
Functional Roles ◽  
Signaling Axis ◽  
Therapy Target ◽  
External Stimuli

The SOS family of Ras-GEFs encompasses two highly homologous and widely expressed members, SOS1 and SOS2. Despite their similar structures and expression patterns, early studies of constitutive KO mice showing that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable led to initially viewing SOS1 as the main Ras-GEF linking external stimuli to downstream RAS signaling, while obviating the functional significance of SOS2. Subsequently, different genetic and/or pharmacological ablation tools defined more precisely the functional specificity/redundancy of the SOS1/2 GEFs. Interestingly, the defective phenotypes observed in concomitantly ablated SOS1/2-DKO contexts are frequently much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells, demonstrating functional redundancy between them and suggesting an ancillary role of SOS2 in the absence of SOS1. Preferential SOS1 role was also demonstrated in different RASopathies and tumors. Conversely, specific SOS2 functions, including a critical role in regulation of the RAS–PI3K/AKT signaling axis in keratinocytes and KRAS-driven tumor lines or in control of epidermal stem cell homeostasis, were also reported. Specific SOS2 mutations were also identified in some RASopathies and cancer forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for consideration as a relevant biomarker/therapy target.

scholarly journals A critical role of AREG for bleomycin-induced skin fibrosis

2021 ◽  
Author(s):  
Mary Yinghua Zhang ◽  
Shuyi Fang ◽  
Hongyu Gao ◽  
Xiaoli Zhang ◽  
Dongsheng Gu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Oral Mucosa ◽  
Healing Process ◽  
Critical Role ◽  
Skin Fibrosis ◽  
Wound Healing Process ◽  
Organ Function ◽  
Signaling Axis

ABSTRACTWe report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

scholarly journals The Role of the N-Domain in the ATPase Activity of the Mammalian AAA ATPase p97/VCP

2012 ◽  
Vol 287 (11) ◽  
pp. 8561-8570 ◽  
Author(s):  
Hajime Niwa ◽  
Caroline A. Ewens ◽  
Chun Tsang ◽  
Heidi O. Yeung ◽  
Xiaodong Zhang ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Aaa Atpase

scholarly journals The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769454 ◽  
Author(s):  
Ming Quan ◽  
Jiu-jie Cui ◽  
Xiao Feng ◽  
Qian Huang
Keyword(s):  
Pancreatic Cancer ◽  
Current Knowledge ◽  
Critical Role ◽  
Treatment Resistance ◽  
G Protein Coupled Receptors ◽  
Signaling Axis ◽  
Tumorigenesis And Progression ◽  
Pathologic Processes ◽  
G Protein Coupled

Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1–6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

Factor XII Contact Activation

2017 ◽  
Vol 43 (08) ◽  
pp. 814-826 ◽  
Author(s):  
Clément Naudin ◽  
Elena Burillo ◽  
Stefan Blankenberg ◽  
Lynn Butler ◽  
Thomas Renné
Keyword(s):  
Critical Role ◽  
Factor Xii ◽  
Contact Activation ◽  
Kinin System ◽  
Disease States ◽  
Charged Surfaces ◽  
Mechanistic Basis ◽  
Kallikrein Kinin System

AbstractContact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation–associated disease states.

scholarly journals Structural and Functional Determinants of Conserved Lipid Interaction Domains of Inward Rectifying Kir6.2 Channels

2002 ◽  
Vol 119 (6) ◽  
pp. 581-591 ◽  
Author(s):  
Catherine A. Cukras ◽  
Iana Jeliazkova ◽  
Colin G. Nichols
Keyword(s):  
Critical Role ◽  
Katp Channels ◽  
Pleckstrin Homology Domain ◽  
Membrane Association ◽  
Kir Channel ◽  
M1 Receptor ◽  
Interaction Domains ◽  
Mechanistic Basis ◽  
Α Helix

All members of the inward rectifiier K+ (Kir) channel family are activated by phosphoinositides and other amphiphilic lipids. To further elucidate the mechanistic basis, we examined the membrane association of Kir6.2 fragments of KATP channels, and the effects of site-directed mutations of these fragments and full-length Kir6.2 on membrane association and KATP channel activity, respectively. GFP-tagged Kir6.2 COOH terminus and GFP-tagged pleckstrin homology domain from phospholipase C δ1 both associate with isolated membranes, and association of each is specifically reduced by muscarinic m1 receptor–mediated phospholipid depletion. Kir COOH termini are predicted to contain multiple β-strands and a conserved α-helix (residues ∼306–311 in Kir6.2). Systematic mutagenesis of D307-F315 reveals a critical role of E308, I309, W311 and F315, consistent with residues lying on one side of a α-helix. Together with systematic mutation of conserved charges, the results define critical determinants of a conserved domain that underlies phospholipid interaction in Kir channels.

scholarly journals The critical role of plasma membrane H+-ATPase activity in cephalosporin C biosynthesis of Acremonium chrysogenum

PLoS ONE ◽  
2020 ◽  
Vol 15 (8) ◽  
pp. e0238452 ◽  
Author(s):  
Alexander Zhgun ◽  
Mariya Dumina ◽  
Ayrat Valiakhmetov ◽  
Mikhail Eldarov
Keyword(s):  
Plasma Membrane ◽  
Atpase Activity ◽  
Critical Role ◽  
Cephalosporin C ◽  
Acremonium Chrysogenum

scholarly journals Kit-Shp2-Kit signaling acts to maintain a functional hematopoietic stem and progenitor cell pool

Blood ◽  
2011 ◽  
Vol 117 (20) ◽  
pp. 5350-5361 ◽  
Author(s):  
Helen He Zhu ◽  
Kaihong Ji ◽  
Nazilla Alderson ◽  
Zhao He ◽  
Shuangwei Li ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Molecular Signaling ◽  
Hematopoietic Stem ◽  
Kit Gene ◽  
Signaling Axis ◽  
Kinase Cascade ◽  
Progenitor Cell Pool

Abstract The stem cell factor (SCF)/Kit system has served as a classic model in deciphering molecular signaling events in the hematopoietic compartment, and Kit expression is a most critical marker for hematopoietic stem cells (HSCs) and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. Herein we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit and other RTKs, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling axis. Inducible ablation of PTPN11/Shp2 resulted in severe cytopenia in BM, spleen, and peripheral blood in mice. Shp2 removal suppressed the functional pool of HSCs/progenitors, and Shp2-deficient HSCs failed to reconstitute lethally irradiated recipients because of defects in homing, self-renewal, and survival. We show that Shp2 regulates coordinately multiple signals involving up-regulation of Kit expression via Gata2. Therefore, this study reveals a critical role of Shp2 in maintenance of a functional HSC/progenitor pool in adult mammals, at least in part through a kinase-phosphatase-kinase cascade.

Sign in / Sign up

Export Citation Format

Share Document