Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance

Liang, Jiyong; Xu, Zhi; Ding, Zhiyong; Lu, Yiling; Yu, Qinghua; Werle, Kaitlin D.; Zhou, Ge; Park, Yun Yong; Peng, Guang; Gambello, Michael J.; Mills, Gordon B.

doi:10.1038/ncomms8926

Cited by 102 publications

(95 citation statements)

References 73 publications

(86 reference statements)

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“…It should be noted that targeting NMT may also lead to inhibition of other NMT downstream proteins in which myristoylation is essential for their function. For example, myristoylation of AMPK is required for its recruitment to the mitochondria for the induction of mitophagy and cell viability (37). The inhibition of B13 on NMT1 activity could potentially block the AMPK recruitment process to inhibit the proliferation of prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

et al. 2017

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Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or post-translational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacological evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell cycle progression, proliferation and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analog B13 as a small molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localizaiton to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its antiinvasive and antitumor effects against prostate cancer cells with minimal toxic side-effects in vivo. Structural optimization based on structure-activity relationships enabled the chemical synthesis of LCL204 with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclincal proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression.

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Section: Discussionmentioning

confidence: 99%

Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

et al. 2017

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“…Autophagy can be triggered through multiple interconnected pathways with the mTOR and AMPK cascades (Liang et al 2015). Our previous research has revealed that the AMPK-mTOR-autophagy signaling cascade in SCs is reversed by the combination of the autophagy inhibitor 3-methyladenine and NP (Duan et al 2016c).…”

Section: Discussionmentioning

confidence: 99%

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Duan

Quan

et al. 2017

Toxicology Letters

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The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100 mg/kg body weight/2 days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis. Furthermore, 10 µM Compound C or AMPKα1 siRNA pre-treatment effectively attenuated autophagy and reversed AMPK-mTOR-p70S6K/4EBP1 signaling in NP-treated SCs. Co-treatment with 1 mM AICAR remarkably strengthened NP-induced autophagy and mTOR inhibition in SCs. Together, these data suggest that NP stimulates Sertoli cell autophagy and inhibits mTOR-p70S6K/4EBP1 activity through AMPK activation, which is the potential mechanism responsible for the regulation of testis function and differentiation following NP exposure.

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“…A majority of tumors develop drug resistant mutants with elevated FGFR activity (30,(40)(41)(42)(43). Among those, mutations of the gatekeeper residues such as FGFR1(V561M) and FGFR3(V555M) have been shown to confer resistance to the multi-kinase inhibitor PP58 and the FGFR inhibitor AZ12908010, respectively (44) (45)(46)(47). Therefore, B13 might target tumor progression in which myristoylation is essential for the "addicted" oncogenic protein in the tumors (48).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression

Li¹,

Alsaidan²,

Ma³

et al. 2018

Journal of Biological Chemistry

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Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance

Cited by 102 publications

References 73 publications

Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Pharmacologically targeting the myristoylation of the scaffold protein FRS2α inhibits FGF/FGFR-mediated oncogenic signaling and tumor progression

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