Research ArticleCholesterol Metabolism

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

See allHide authors and affiliations

Sci. Signal.  03 Nov 2015:
Vol. 8, Issue 401, pp. ra111
DOI: 10.1126/scisignal.aac5124

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Providing cholesterol for proliferation

Although cholesterol has received a lot of bad press, this lipid molecule is actually an essential component of cellular membranes. Growing or dividing cells need more cholesterol than quiescent cells. The activity of epidermal growth factor receptor (EGFR) family members stimulates cell proliferation in physiological and pathophysiological contexts, such as cancer. Haskins et al. found that neuregulin 1 (NRG1)–mediated activation of the EGFR member ERBB4 stimulated the transcription factor SREBP-2, which enhanced the expression of the receptor needed to uptake cholesterol-rich low-density lipoproteins and genes involved in cholesterol biosynthesis in cultured breast epithelial cells. Pharmacological inhibition of EGFR activity or SREBP-2 activity suppressed the NRG1-mediated induction of cholesterol synthesis–related genes. Thus, EGFR signaling alters cellular lipid metabolism, enabling cells to acquire or synthesize molecules necessary for proliferation.

Abstract

Cholesterol is a lipid that is critical for steroid hormone production and the integrity of cellular membranes, and, as such, it is essential for cell growth. The epidermal growth factor receptor (EGFR) family member ERBB4, which forms signaling complexes with other EGFR family members, can undergo ligand-induced proteolytic cleavage to release a soluble intracellular domain (ICD) that enters the nucleus to modify transcription. We found that ERBB4 activates sterol regulatory element binding protein-2 (SREBP-2) to enhance low-density lipoprotein (LDL) uptake and cholesterol biosynthesis. Expression of the ERBB4 ICD in mammary epithelial cells or activation of ERBB4 with the ligand neuregulin 1 (NRG1) induced the expression of SREBP target genes involved in cholesterol biosynthesis, including HMGCR and HMGCS1, and lipid uptake, LDLR, which encodes the LDL receptor. Addition of NRG1 increased the abundance of the cleaved, mature form of SREBP-2 through a pathway that was blocked by addition of inhibitors of PI3K (phosphatidylinositol 3-kinase) or dual inhibition of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, but not by inhibition of AKT or mTORC1. Pharmacological inhibition of the activity of SREBP site 1 protease or of all EGFR family members (with lapatinib), but not EGFR alone (with erlotinib), impaired NRG1-induced expression of cholesterol biosynthesis genes. Collectively, our findings indicated that activation of ERBB4 promotes SREBP-2–regulated cholesterol metabolism. The connections of EGFR and ERBB4 signaling with SREBP-2–regulated cholesterol metabolism are likely to be important in ERBB-regulated developmental processes and may contribute to metabolic remodeling in ERBB-driven cancers.

View Full Text