Browsing by Author "Lin, Hui-Kuan"

Now showing 1 - 7 of 7
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    EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.
    (The Journal of clinical investigation, 2014-09) Feng, Haizhong; Lopez, Giselle Y; Kim, Chung Kwon; Alvarez, Angel; Duncan, Christopher G; Nishikawa, Ryo; Nagane, Motoo; Su, An-Jey A; Auron, Philip E; Hedberg, Matthew L; Wang, Lin; Raizer, Jeffery J; Kessler, John A; Parsa, Andrew T; Gao, Wei-Qiang; Kim, Sung-Hak; Minata, Mutsuko; Nakano, Ichiro; Grandis, Jennifer R; McLendon, Roger E; Bigner, Darell D; Lin, Hui-Kuan; Furnari, Frank B; Cavenee, Webster K; Hu, Bo; Yan, Hai; Cheng, Shi-Yuan
    Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.
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    Identification of myo-inositol-binding proteins by using the biotin pull-down strategy in cultured cells.
    (STAR protocols, 2022-06) Hsu, Che-Chia; Xu, Zhi-Gang; Lei, Jie; Chen, Zhong-Zhu; Li, Hong-Yu; Lin, Hui-Kuan
    Metabolites are not only substrates in metabolic reactions, but they also serve as signaling molecules to regulate diverse biological functions. Identification of the binding proteins for the metabolites helps in the understanding of their functions beyond the classic metabolic pathways in which they are involved. We provide the protocol for synthesizing the biotin-labeled myo-inositol, which is used to identify its binding proteins by using biotin pull-down assay, given there is no available tool for the rapid screening of inositol-binding proteins in cells and in vitro systems. Biotin-labeled inositol probe therefore provides a tool to identify inositol's sensors. For complete details on the use and execution of this protocol, please refer to Hsu et al. (2021).
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    Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.
    (Molecular cell, 2021-09) Hsu, Che-Chia; Zhang, Xian; Wang, Guihua; Zhang, Weina; Cai, Zhen; Pan, Bo-Syong; Gu, Haiwei; Xu, Chuan; Jin, Guoxiang; Xu, Xiangshang; Manne, Rajesh Kumar; Jin, Yan; Yan, Wei; Shao, Jingwei; Chen, Tingjin; Lin, Emily; Ketkar, Amit; Eoff, Robert; Xu, Zhi-Gang; Chen, Zhong-Zhu; Li, Hong-Yu; Lin, Hui-Kuan
    Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.
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    Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS
    (Cell, 2019-06) Zhang, Weina; Wang, Guihua; Xu, Zhi-Gang; Tu, Haiqing; Hu, Fuqing; Dai, Jiang; Chang, Yan; Chen, Yaqi; Lu, Yanjun; Zeng, Haolong; Cai, Zhen; Han, Fei; Xu, Chuan; Jin, Guoxiang; Sun, Li; Pan, Bo-Syong; Lai, Shiue-Wei; Hsu, Che-Chia; Xu, Jia; Chen, Zhong-Zhu; Li, Hong-Yu; Seth, Pankaj; Hu, Junbo; Zhang, Xuemin; Li, Huiyan; Lin, Hui-Kuan
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    Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.
    (Cell reports, 2023-01) Meyers, Allison K; Wang, Zhan; Han, Wenzheng; Zhao, Qingxia; Zabalawi, Manal; Duan, Likun; Liu, Juan; Zhang, Qianyi; Manne, Rajesh K; Lorenzo, Felipe; Quinn, Matthew A; Song, Qianqian; Fan, Daping; Lin, Hui-Kuan; Furdui, Cristina M; Locasale, Jason W; McCall, Charles E; Zhu, Xuewei
    Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggests a non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.
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    SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.
    (The Journal of clinical investigation, 2022-03) Xu, Chuan; Jin, Guoxiang; Wu, Hong; Cui, Wei; Wang, Yu-Hui; Manne, Rajesh Kumar; Wang, Guihua; Zhang, Weina; Zhang, Xian; Han, Fei; Cai, Zhen; Pan, Bo-Syong; Hsu, Che-Chia; Liu, Yiqiang; Zhang, Anmei; Long, Jie; Zou, Hongbo; Wang, Shuang; Ma, Xiaodan; Duan, Jinling; Wang, Bin; Liu, Weihui; Lan, Haitao; Xiong, Qing; Xue, Gang; Chen, Zhongzhu; Xu, Zhigang; Furth, Mark E; Haigh Molina, Sarah; Lu, Yong; Xie, Dan; Bian, Xiu-Wu; Lin, Hui-Kuan
    Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.
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    The Skp2 Pathway: A Critical Target for Cancer Therapy.
    (Seminars in cancer biology, 2020-12) Cai, Zhen; Moten, Asad; Peng, Danni; Hsu, Che-Chia; Pan, Bo-Syong; Manne, Rajeshkumar; Li, Hong-Yu; Lin, Hui-Kuan
    Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.