Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake

Haskins, Jonathan W.; Zhang, Shannon; Means, Robert E.; Kelleher, Joanne K.; Cline, Gary W.; Canfrán‐Duque, Alberto; Suárez, Yajaira; Stern, David F.

doi:10.1126/scisignal.aac5124

Cited by 37 publications

(31 citation statements)

References 57 publications

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“…Such metabolic adaptation allows glioma cells to sustain lipid biosynthesis and to limit ROS toxicity in the absence of growth factor signaling. Furthermore, the connection between RTK signaling and lipid metabolism has been extensively studied, linking RTKs, including ERBB4, EGFR, and FGFR3, to enhanced fatty acid and cholesterol biosynthesis (Haskins et al, 2015; Bian et al, 2015; Du et al, 2012). In particular, the EGFR/PI3K/Akt axis promotes GBM tumor growth in part through SREBP1-driven upregulation of acetyl-CoA carboxylase (ACC), FAS, and low-density lipoprotein receptor (LDLR) (Guo et al, 2009b; Guo et al, 2009a; Guo et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

et al. 2017

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Summary Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBM. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBM to support macromolecular synthesis, aggressive growth, and therapy resistance.

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Section: Discussionmentioning

confidence: 99%

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

et al. 2017

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“…The function of SREBP-1 has been investigated in multiple cancer cell lines including colon [70], lung [71] and pancreatic cancer cell lines [72]. SREBP-2 has been shown to be upregulated in prostate cancer patient tumor tissues (Table 1) [73], and elevated by ERBB4 signaling in breast cancer cells [74]. Moreover, SREBP-2 is also activated by Akt in Chinese hamster ovary-7 (CHO-7) and CHO cells [75].…”

Section: Activation Of Scap/srebps In Cancermentioning

confidence: 99%

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Cheng

Guo

2018

CTMC

102

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Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavage-activating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

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“…A nanoscale reverse-phase HPLC capillary column was created by packing 2.6-m C18 spherical silica beads into a fused silica capillary (100 m inner diameter ϫ ϳ25 cm length) with a flame-drawn tip (28). After equilibrating the column, each sample was loaded via a Famos autosampler (LC Packings, San Francisco, CA) onto the column.…”

Section: Methods For Phosphorylation Analysis By Lc/ms-msexcised Gel mentioning

confidence: 99%

Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex

Gerarduzzi¹,

Polo²,

Liu³

et al. 2016

Journal of Biological Chemistry

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Edited by Eric FearonDeregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes. Using a phospho-proteomics approach, we functionally identified a novel Her4-induced posttranslational modification on MDMX at Ser-314, a putative phosphorylation site for the CDK4/6 kinase. Remarkably, inhibition of Ser-314 phosphorylation either with Ser-to-Ala substitution or with a specific inhibitor of CDK4/6 kinase blocked Her4-induced stabilization of MDMX-MDM2 and rescued p53 activity. Our study offers insights into the mechanisms of deregulated RTK-induced carcinogenesis and provides the basis for the use of inhibitors targeting RTKmediated signals for p53 restoration. p53 is either mutated or functionally inactive in most human cancers. Several tumor types that retain wild-type p53 (i.e. breast cancer) display higher protein levels of MDMX and/or MDM2 2 (1-8), the primary inhibitors of p53, representing alternative mechanisms of p53 inactivation. Typically, p53 protein levels are tightly controlled and modulated by its principle negative regulator, the MDMX-MDM2 complex. Given that MDMX and MDM2 are amplified in many tumors, modulation of their stability offers an attractive therapeutic strategy to restore p53 function and so improve tumor responsiveness to DNA-damaging therapy.Although MDM2 is the main negative regulator of p53, there is now growing evidence supporting the notion that MDMX also plays a key role in modulating p53, mainly through its stabilization of MDM2 (9). In fact, the MDMX-MDM2 heterocomplex is the main form in which the two proteins are found in the cell (10, 11), and loss of this formation leads to p53 activation and embryonic lethality (9, 11-13).Under non-stressed conditions, MDMX and MDM2 suppress p53 activity. However, under stress conditions, MDMX and MDM2 are posttranslationally modified and disabled for their inhibition of p53. As a result, p53 can then respond to the stress and repair any damage. MDM2 and MDMX are structural homologs, with the major distinction that MDM2 contains an E3 ligase domain, a nuclear localization signal domain, and a nuclear export signal domain (14). There are two major ways in which p53 activity can be suppressed by the complex. First, MDM2 and MDMX can cooperatively bind to the transactivational domain of p53 and suppress its transcriptional activity. Second, MDM2 can act as an E3 ligase and induce p53 ubiquitination an...

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Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake

Cited by 37 publications

References 57 publications

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex

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