scholarly journals Paraneoplastic Focal Segmental Glomerulosclerosis Associated With Gastrointestinal Stromal Tumors With Cutaneous Metastasis: a Case Report

2021 ◽  
Author(s):  
Jun Zhou ◽  
Zhen Yang ◽  
Cuishun Yang ◽  
Hua Lin ◽  
Wanqiong Yuan
Keyword(s):  
Nephrotic Syndrome ◽  
Case Report ◽  
Focal Segmental Glomerulosclerosis ◽  
Hippo Pathway ◽  
Symptomatic Treatment ◽  
Cutaneous Metastasis ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Segmental Glomerulosclerosis ◽  
The Hippo Pathway

Abstract Background: Gastrointestinal stromal tumor (GIST) is one of most common mesenchymal neoplasms occurring in different areas of the gastrointestinal tract. GISTs with cutaneous metastasis is very rare and its rarity cutaneous GISTs have not been well characterized. Focal segmental glomerulosclerosis (FSGS) is also rare among paraneoplastic nephritic syndromes (PNS).Case presentation: In this case report, we described a 64-year-old patient with cutaneous metastasis GIST accompanied by nephrotic syndrome as PNS, in whom symptomatic treatment was ineffective, but clinical remission was achieved after surgery. Moreover, the patient has a missense mutation of NPHP4. NPHP4 served as a negative regulator of the Hippo pathway. Hippo signaling pathway is involved in the development and progression of FSGS. NPHP4 is also indeed a driving force for proliferation in tumor cells. Therefore, the mutation of NPHP4 in this patient could explain the occurrence of GIST and FSGS and this was therefore not a random association.Conclusions: This is the first reported case of a GIST with cutaneous metastasis accompanied by nephrotic syndrome as PNS.

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

scholarly journals Adhesion to fibronectin regulates Hippo signaling via the FAK–Src–PI3K pathway

2015 ◽  
Vol 210 (3) ◽  
pp. 503-515 ◽  
Author(s):  
Nam-Gyun Kim ◽  
Barry M. Gumbiner
Keyword(s):  
Hippo Pathway ◽  
Growth Factor Receptor ◽  
Pi3k Pathway ◽  
Negative Regulator ◽  
Nuclear Accumulation ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Large Tumor ◽  
Inhibition Of Proliferation ◽  
The Hippo Pathway

The Hippo pathway is involved in the regulation of contact inhibition of proliferation and responses to various physical and chemical stimuli. Recently, several upstream negative regulators of Hippo signaling, including epidermal growth factor receptor ligands and lysophosphatidic acid, have been identified. We show that fibronectin adhesion stimulation of focal adhesion kinase (FAK)-Src signaling is another upstream negative regulator of the Hippo pathway. Inhibition of FAK or Src in MCF-10A cells plated at low cell density prevented the activation of Yes-associated protein (YAP) in a large tumor suppressor homologue (Lats)–dependent manner. Attachment of serum-starved MCF-10A cells to fibronectin, but not poly-d-lysine or laminin, induced YAP nuclear accumulation via the FAK–Src–phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) signaling pathway. Attenuation of FAK, Src, PI3K, or PDK1 activity blocked YAP nuclear accumulation stimulated by adhesion to fibronectin. This negative regulation of the Hippo pathway by fibronectin adhesion signaling can, at least in part, explain the effects of cell spreading on YAP nuclear localization and represents a Lats-dependent component of the response to cell adhesion.

scholarly journals Nuclear exclusion of YAP exacerbates podocyte apoptosis and disease progression in Adriamycin-induced focal segmental glomerulosclerosis

2020 ◽  
Author(s):  
Qiyuan Zhuang ◽  
Fang Li ◽  
Jun Liu ◽  
Hongyu Wang ◽  
Yuchen Tian ◽  
...  
Keyword(s):  
Mouse Model ◽  
Disease Progression ◽  
Focal Segmental Glomerulosclerosis ◽  
Hippo Pathway ◽  
Control Cell ◽  
Segmental Glomerulosclerosis ◽  
Nuclear Exclusion ◽  
The Hippo Pathway

AbstractFocal segmental glomerulosclerosis (FSGS) is a chronic glomerular disease with poor clinical outcomes. Podocyte loss via apoptosis is one important mechanism underlying the pathogenesis of FSGS. Recently, Yes-associated-protein (YAP), a key downstream protein in the Hippo pathway, was identified as an activator for multiple gene transcriptional factors in the nucleus to control cell proliferation and apoptosis. To investigate the potential role of YAP in the progression of FSGS, we examined kidney samples from patients with minimal change disease or FSGS and found that increases in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in human FSGS. Utilizing an established mT/mG transgenic mouse model and primary cultured podocytes, we found that YAP was distributed uniformly in nucleus and cytoplasm in the podocytes of control animals. Adriamycin treatment induced gradual nuclear exclusion of YAP with enhanced phospho-YAP/YAP ratio, accompanied by the induction of podocyte apoptosis both in vivo and in vitro. Moreover, we used verteporfin to treat an Adriamycin-induced FSGS mouse model, and found YAP inhibition by verteporfin induced nuclear exclusion of YAP, thus increasing podocyte apoptosis and accelerating disease progression. Therefore, our findings suggest that YAP nuclear distribution and activation in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS.

scholarly journals Clinical manifestations of focal segmental glomerulosclerosis in Japan from the Japan Renal Biopsy Registry: age stratification and comparison with minimal change disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takaya Ozeki ◽  
Shoichi Maruyama ◽  
Toshiyuki Imasawa ◽  
Takehiko Kawaguchi ◽  
Hiroshi Kitamura ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Renal Biopsy ◽  
Focal Segmental Glomerulosclerosis ◽  
Clinical Diagnosis ◽  
Clinical Characteristics ◽  
Minimal Change Disease ◽  
Multivariable Analysis ◽  
Laboratory Data ◽  
Minimal Change ◽  
Segmental Glomerulosclerosis

AbstractFocal segmental glomerulosclerosis (FSGS) is a serious condition leading to kidney failure. We aimed to investigate the clinical characteristics of FSGS and its differences compared with minimal change disease (MCD) using cross-sectional data from the Japan Renal Biopsy Registry. In Analysis 1, primary FSGS (n = 996) were stratified by age into three groups: pediatric (< 18 years), adult (18–64 years), and elderly (≥ 65 years), and clinical characteristics were compared. Clinical diagnosis of nephrotic syndrome (NS) was given to 73.5% (97/132) of the pediatric, 41.2% (256/622) of the adult, and 65.7% (159/242) of the elderly group. In Analysis 2, primary FSGS (n = 306) and MCD (n = 1303) whose clinical diagnosis was nephrotic syndrome (NS) and laboratory data were consistent with NS, were enrolled. Logistic regression analysis was conducted to elucidate the variables which can distinguish FSGS from MCD. On multivariable analysis, higher systolic blood pressure, higher serum albumin, lower eGFR, and presence of hematuria associated with FSGS. In Japanese nationwide registry, primary FSGS patients aged 18–64 years showed lower rate of NS than those in other ages. Among primary nephrotic cases, FSGS showed distinct clinical features from MCD.

Sign in / Sign up

Export Citation Format

Share Document