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Jarugumilli, Gopala

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Jarugumilli

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Gopala

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Jarugumilli, Gopala

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2016 - 20193

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Author's Publications: search.filters.isAuthorOfPublication.e760774a-882e-48b1-a506-1ff16b4da9dd

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    Autopalmitoylation of TEAD Proteins Regulates Transcriptional Output of Hippo Pathway
    (2016) Chan, PuiYee; Han, Xiao; Zheng, Baohui; DeRan, Michael; Yu, Jianzhong; Jarugumilli, Gopala; Deng, Hua; Pan, Duojia; Luo, Xuelian; Wu, Xu
    TEA domain (TEAD) transcription factors bind to the co-activator YAP/TAZ, and regulate the transcriptional output of Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches fatty acid (palmitate) to cysteine residues, and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme-like activities, and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs, and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation is required for TEAD’s binding to YAP/TAZ, but dispensable for the binding to Vgll4 tumor suppressor. In addition, palmitoylation does not alter TEAD’s localization. Moreover, TEAD palmitoylation-deficient mutants impaired TAZ-mediated muscle differentiation in vitro, and Yorkie-mediated tissue overgrowth in Drosophila in vivo. Our study directly linked autopalmitoylation to the transcriptional regulation of Hippo pathway.
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    ZDHHC7-Mediated S-Palmitoylation of Scribble Regulates Cell Polarity
    (2016) Chen, Baoen; Zheng, Baohui; DeRan, Micael; Jarugumilli, Gopala; Fu, Jianjun; Brooks, Yang S.; Wu, Xu
    Scribble (SCRIB) is a tumor suppressor protein, playing critical roles in establishing and maintaining epithelial cell polarity. Paradoxically, SCRIB is frequently amplified in human cancers, however, fails to localize properly to cell-cell junctions, suggesting that mislocalization of SCRIB contributes to tumorigenesis. Using chemical reporters, here we showed that SCRIB localization is regulated by S-palmitoylation at conserved cysteine residues. The palmitoylation-deficient mutants of SCRIB are mislocalized, leading to disruption of cell polarity and loss of their tumor suppressive activities to oncogenic YAP, MAPK and PI3K/Akt pathways. We further found that ZDHHC7 is the major palmitoyl acyltransferase regulating SCRIB. Knockout of ZDHHC7 led to SCRIB mislocalization and YAP activation, and disruption of SCRIB’s suppressive activities in HRasV12-induced cell invasion. In summary, we demonstrated that ZDHHC7-mediated SCRIB palmitoylation is critical for SCRIB membrane targeting, cell polarity, and tumor suppression, providing new mechanistic insights of how dynamic protein palmitoylation regulates cell polarity and tumorigenesis.
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    Fatty Acids and Cancer-Amplified ZDHHC19 Promote STAT3 Activation Through S-Palmitoylation
    (Springer Science and Business Media LLC, 2019-08-28) Niu, Jixiao; Sun, Yang; Chen, Baoen; Mino-Kenudson, Mari; Zheng, Baohui; Jarugumilli, Gopala; Walker, Sarah; Hata, Aaron; David, Frank; Wu, Xu
    Signal transducer and activator of transcription 3 (STAT3) plays a critical role in regulating cell fate, inflammation and immunity. Cytokines and growth factors activate STAT3 through kinase-mediated tyrosine phosphorylation and dimerization. It remains unknown whether other factors could promote STAT3 activation through different mechanisms. Here we show that STAT3 is posttranslationally S-palmitoylated at the Src Homology 2 (SH2) domain, promoting its dimerization and transcriptional activation. Fatty acids could directly activate STAT3 by enhancing its palmitoylation, in synergy with cytokine stimulation. We further identified ZDHHC19 as a palmitoyl acyltransferase (PAT) regulating STAT3. Cytokine stimulation enhances STAT3 palmitoylation by promoting ZDHHC19–STAT3 association mediated by Grb2 SH3 domain. Silencing ZDHHC19 blocks STAT3 palmitoylation and dimerization, impairing cytokine and fatty acid-induced STAT3 activation. Importantly, ZDHHC19 is frequently amplified in multiple human cancers, including in 39% of lung squamous cell carcinomas (LSCCs). High ZDHHC19 levels correlate with high nuclear STAT3 in patient samples. In addition, ZDHHC19 knockout in LSCC cells significantly blocks STAT3 activity, and inhibits fatty acid-induced tumorsphere formation and high-fat diet (HFD)-induced tumorigenesis in vivo. Taken together, we reveal that fatty acid and ZDHHC19-mediated palmitoylation are additional signals regulating STAT3, linking deregulation of palmitoylation to inflammation and cancer.