1,439 research outputs found
Willin, an upstream component of the Hippo signaling pathway, orchestrates mammalian peripheral nerve fibroblasts
No full textWillin/FRMD6 was first identified in the rat sciatic nerve, which is composed of neurons, Schwann cells, and fibroblasts. Willin is an upstream component of the Hippo signaling pathway, which results in the inactivation of the transcriptional coactivator YAP through Ser127 phosphorylation. This in turn suppresses the expression of genes involved in cell growth, proliferation and cancer development ensuring the control of organ size, cell contact inhibition and apoptosis. Here we show that in the mammalian sciatic nerve, Willin is predominantly expressed in fibroblasts and that Willin expression activates the Hippo signaling cascade and induces YAP translocation from the nucleus to the cytoplasm. In addition within these cells, although it inhibits cellular proliferation, Willin expression induces a quicker directional migration towards scratch closure and an increased expression of factors linked to nerve regeneration. These results show that Willin modulates sciatic nerve fibroblast activity indicating that Willin may have a potential role in the regeneration of the peripheral nervous system.Peer reviewe
Oral History Interview with Patrick F. Ryan
No full textPatrick F. Ryan, Navy, (Amphibious Force),Gunner’s mate, third class USNR, USS Clay PA 39, USS Knox PA 46.
Ryan’s job was the invasion force, taking the Army & Navy troops into the beaches. Involved in Philippine liberation invasion of Leyte & Luzon Asiatic Pacific invasions of Saipan, Tinian, Yap and Iwo Jima.https://vc.bridgew.edu/vhp_stories/1007/thumbnail.jp
Expanding the Hippo pathway : hMOB3 modulates apoptotic MST1 signaling and supports tumor growth in glioblastoma
No full textProtein kinases are critical players of signal transduction pathways involved in development, physiological and pathological processes. Deregulation of protein kinase signaling is found to be causal or related to varieties of human diseases, such as cancer, cardiovascular disease and diabetes. The human genome encodes 518 protein kinases. Approximately 60 out of them belong to the AGC group of Serine/Threonine protein kinases, including the ste20 like MST kinase family and NDR kinase family. Members of these families are highly conserved from yeast to men and regulate essential processes such as growth, proliferation and apoptosis. The Hippo pathway is a recently identified tumor suppressive network, where the MST-NDR family kinases form a kinase cascade regulating the downstream signaling through the effector YAP/TAZ.
In addition to signaling through the NDR family kinases, the Hippo/MST kinases also control cell apoptosis bypass these classical effectors YAP/TAZ. Despite the fact that JNK, FOXO3, H2B are well characterized downstream targets of apoptotic MST kinases, the regulatory mechanisms of apoptotic MST signaling are still largely unknown.
The human MOB family consists of six members encoded by six different genes (hMOB1A, -1B, -2, -3A, -3B and -3C). While as an activator for hMOB1A/B in MST-LATS/NDR kinase cascade, hMOB2 is a specific negative regulator of NDR kinase by competing the binding of hMOB1 to NDR kinase. Although hMOB3 family members share higher amino acid identity with hMOB1 than hMOB2, hMOB3 proteins do not interact or (de)activate NDR family kinases. Hence, the functions of hMOB3A/B/C are completely undefined.
A previous microarray study performed in the lab indicated that hMOB3 family members were deregulated in glioblastoma. In the present study, we first investigated the pathological roles of human MOB3 proteins and found that hMOB3 is highly upregulated in glioblastoma. Moreover, mRNA expression levels of hMOB3 members correlate with survival, suggesting hMOB3 members as potential prognostic markers. We extended the biochemical analysis by looking for the interaction partners of hMOB3 and demonstrated that hMOB3 binds to MST1 and inhibits the apoptotic cleavage of MST1 kinase. We further verified that hMOB3 promotes tumorigenesis of gliobalstoma cells in vivo by a U87MG derived flank model. Taken together, our results suggest that manipulate hMOB3 might represent a therapeutic strategy in malignant gliomas
MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration
No full textSummaryThe pulmonary alveolar epithelium undergoes extensive regeneration in response to lung injuries, including lung resection. In recent years, our understanding of cell lineage relationships in the pulmonary alveolar epithelium has improved significantly. However, the molecular and cellular mechanisms that regulate pneumonectomy (PNX)-induced alveolar regeneration remain largely unknown. In this study, we demonstrate that mechanical-tension-induced YAP activation in alveolar stem cells plays a major role in promoting post-PNX alveolar regeneration. Our results indicate that JNK and p38 MAPK signaling is critical for mediating actin-cytoskeleton-remodeling-induced nuclear YAP expression in alveolar stem cells. Moreover, we show that Cdc42-controlled actin remodeling is required for the activation of JNK, p38, and YAP in post-PNX lungs. Our findings together establish that the Cdc42/F-actin/MAPK/YAP signaling cascade is essential for promoting alveolar regeneration in response to mechanical tension in the lung
The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain
No full textThe transcriptional coactivator Yes-associated protein (YAP) is a major regulator of organ size and proliferation in vertebrates. As such, YAP can act as an oncogene in several tissue types if its activity is increased aberrantly. Although no activating mutations in the yap1 gene have been identified in human cancer, yap1 is located on the 11q22 amplicon, which is amplified in several human tumors. In addition, mutations or epigenetic silencing of members of the Hippo pathway, which represses YAP function, have been identified in human cancers. Here we demonstrate that, in addition to increasing tumor growth, increased YAP activity is potently prometastatic in breast cancer and melanoma cells. Using a Luminex-based approach to multiplex in vivo assays, we determined that the domain of YAP that interacts with the TEAD/TEF family of transcription factors but not the WW domains or PDZ-binding motif, is essential for YAP-mediated tumor growth and metastasis. We further demonstrate that, through its TEAD-interaction domain, YAP enhances multiple processes known to be important for tumor progression and metastasis, including cellular proliferation, transformation, migration, and invasion. Finally, we found that the metastatic potential of breast cancer and melanoma cells is strongly correlated with increased TEAD transcriptional activity. Together, our results suggest that increased YAP/TEAD activity plays a causal role in cancer progression and metastasis.Howard Hughes Medical InstituteNational Institutes of Health (U.S.)David H. Koch Institute for Integrative Cancer Research at MITNational Cancer Institute (U.S.) (Integrative Center Biology Program)National Institutes of Health (U.S.) (Tumor Microenvironment Network)National Institutes of Health (U.S.) (National Research and Service Award)National Cancer Institute (U.S.) (Postdoctoral fellowship)Massachusetts Institute of Technology. Ludwig Center for Molecular Oncology (Ludwig Graduate Fellowship
Enigma proteins regulate YAP mechanotransduction
No full textHuman cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.This article has an associated First Person interview with the first author of the paper
Inhibition of YAP ameliorates renal fibrosis through FGF2 pathway
No full textThe Hippo pathway is an evolutionarily conserved kinase cascade that controls organ size by regulating cell proliferation, differentiation, migration, and apoptosis. Activation of the Hippo pathway leads to the phosphorylation of mammalian Ste20-like kinases 1/2 (MST1/2) and large tumor suppressor 1/2 (LAT1/2), the latter in turn inhibits the core effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through phosphorylation and thus inhibiting their nuclear localization. On the other hand, inactivation of the Hippo pathway leads to YAP/TAZ activation through promoting YAP/TAZ dephosphorylation and nuclear retention. Once activated, YAP/TAZ interact with TEAD or other transcription factors to induce the expression of a wide range of their downstream genes. Recently, the protein level of YAP was reported to be higher in the kidney of diabetic mice and in renal proximal tubule epithelial cells in response to high glucose, indicating that YAP may play a role in the pathogenesis of diabetic kidney disease.In the present study, we observed that the expression of both YAP and fibroblast growth factor 2 (FGF2) is higher in kidneys of diabetic db/db mice. Oral gavage of atorvastatin (10 mg/kg/daily), a lipid-lowering drug with newly identified YAP inhibitory property, alleviates albuminuria, glomerular hypertrophy, and renal fibrosis in db/db mice, accompanied by reduced renal expression of YAP and FGF2. To investigate whether hyperglycemia in diabetic conditions promotes YAP activation and FGF2 over-expression in kidney cells, we treated human proximal renal tubular epithelial cells (HK2) with 30 mM glucose for 48 hours and found that high glucose increased the mRNA level of YAP target genes (ANKRD1, CTGF, and CYR61) and FGF2. To explore if YAP/TAZ control the FGF2 expression, we transfected HK2 cells with plasmids expressing YAP/TAZ and showed that both expression and secretion of FGF2 were induced by YAP/TAZ over-expression. Oppositely, knockdown of YAP/TAZ decreased the expression of FGF2. The FGF2-promoter reporter gene assay further confirmed that YAP/TAZ promote the FGF2 expression at the transcriptional level. To investigate the effect of YAP activation in renal fibrosis, we constructed the Ksp-Cre transgenic MST1/MST2 double knockout (dKO) mice to achieve kidney-specific YAP activation. The results revealed that the expression of FGF2 is increased in dKO mice accompanied by renal fibrosis development at 8 weeks of age. While tubular-specific MST1/MST2/YAP triple knockout (tKO) mice were partly rescued from renal fibrosis in dKO mice with decreased expression of FGF2. To further clarify if FGF2 mediates YAP/TAZ-induced renal fibrosis, we injected the renal pelvis of dKO mice with the adeno-associated virus carrying CRISPR/Cas9-mediated FGF2 knockdown sequences. As the results showed, one month after virus injection, the FGF2 expression was significantly decreased and the renal fibrosis was ameliorated in the mouse kidneys. Taken together, the present results suggest that YAP activation promotes renal fibrosis through inducing the FGF2 expression and inhibition of YAP ameliorate renal fibrosis partly through decreasing the expression of FGF2.Hippo信號通路是壹條進化上非常保守的信號通路，通過調節細胞增殖，分化，遷移和雕亡來控制器官的大小。 Hippo信號通路的激活導致哺乳動物MST1 / 2激酶和腫瘤抑制因子LAT1 / 2的磷酸化，最終抑制了轉錄共激活因子 YAP 和 TAZ，通過磷酸化作用抑制其入核。另壹方面，Hippo信號通路的失活通過促進YAP / TAZ去磷酸化和入核而導致YAP / TAZ活化。激活後，YAP / TAZ與TEAD或其他轉錄因子相互作用，並誘導其下遊基因的廣泛表達。研究發現，糖尿病小鼠的腎臟和高糖刺激的人近端腎小管上皮細胞中YAP激活，這表明YAP可能參與糖尿病腎病的發病機理。在本研究中，我們發現糖尿病小鼠（db/db）腎臟中的YAP和FGF2表達升高。應用壹種具有YAP抑制特性的降脂藥物阿托伐他汀灌胃（10 mg / kg / 每日），可抑制YAP和FGF2表達，並減輕db/db小鼠的蛋白尿，腎小球肥大和腎纖維化。為了研究糖尿病患者中的高血糖是否促進YAP激活和FGF2的表達，我們用30 mM葡萄糖處理人近端腎小管上皮細胞（HK2）48小時，發現高糖會增加YAP靶基因（ANKRD1，CTGF和CYR61）和FGF2的表達。為了探討YAP / TAZ是否調控FGF2的表達，我們在HK2細胞中過表達YAP / TAZ，發現 YAP / TAZ過表達誘導了FGF2的表達和分泌。相反，YAP / TAZ 敲低降低了FGF2的表達。 FGF2-啟動子報告基因檢測進壹步證實了YAP/TAZ 在轉錄水平調節FGF2表達。為了研究YAP激活在腎纖維化中的作用，我們構建了腎小管特異性MST1 / MST2雙敲除（dKO）小鼠，以實現腎小管特異性YAP激活。實驗結果表明，在8周齡的dKO小鼠中，伴隨著腎纖維化的發展，FGF2的表達增加。腎小管特異性MST1 / MST2 / YAP三重敲除（tKO）小鼠，FGF2的表達下調，腎纖維化有所緩解。為了進壹步闡明FGF2是否參與YAP / TAZ誘導的腎纖維化，我們用帶有CRISPR / Cas9介導的FGF2敲除序列的腺相關病毒對dKO小鼠進行腎盂註射。結果表明，註射後1個月，FGF2表達顯著降低，腎纖維化得到改善。綜上所述，這些結果表明YAP活化通過誘導FGF2表達促進腎纖維化，阿托伐他汀對YAP的抑制可以部分通過降低FGF2的表達改善腎纖維化。Wang, Yu."December 2020."Ph.D. Chinese University of Hong Kong 2021.Includes bibliographical references (leaves 113-121).Abstracts also in Chinese.Title from PDF title page (viewed on September 13, 2022)
Enigma proteins regulate YAP mechanotransduction
No full textHuman cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction.This article has an associated First Person interview with the first author of the paper
Mathematical Modeling of the YAP/TAZ Pathways
No full textabstract: YAP/TAZ is the key effector in the Hippo pathway, but it is also involved in many other regulatory pathways to control tissue and organ size. To better understand its regulation and effects in tumorigenesis and degeneration, a preliminary feedback network was created with the species YAP/TAZ, phosphorylated YAP/TAZ, LATS, miR-130a, VGLL4, and β-catenin. From this network a set of ordinary differential equations were written and analyzed for parameter effects. A model showing the healthy, tumorigenic, and degenerative states was created and preliminary parameter analysis identified the effects of parameter modifications on the overall levels of YAP/TAZ. Further analysis is required and connections with the underlying biology should continue to be pursued to better understand how parameter modifications could improve disease treatments
1H, 13C, 15N resonance assignment of human YAP 50–171 fragment
No full textYes associated protein (YAP) is an intrinsically disordered protein that plays a major role in the Hippo pathway, regulating organ size, cell proliferation, apoptosis, and is associated with cancer development. Therefore, the binding between YAP and TEAD is an interesting target for cancer therapy. The TEAD binding domain of YAP was mapped to protein residues 50–171. To obtain further structural insights into this 12 kDa segment of YAP, we report a backbone and a partial sidechain assignment of recombinant YAP 50–171.© The Author(s) 201
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