Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells

Abstract

Lrp5 is typically described as a Wnt signaling receptor, albeit a less effective Wnt signaling receptor than the better-studied sister isoform, Lrp6. Here we show that Lrp5 is only a minor player in the response to Wnt3a-type ligands in mammary epithelial cells; instead, Lrp5 is required for glucose uptake, and glucose uptake regulates the growth rate of mammary epithelial cells in culture. Thus, a loss of Lrp5 leads to profound growth suppression, whether growth is induced by serum or by specific growth factors, and this inhibition is not due to a loss of Wnt signaling. Depletion of Lrp5 decreases glucose uptake, lactate secretion, and oxygen consumption rates; inhibition of glucose consumption phenocopies the loss of Lrp5 function. Both Lrp5 knockdown and low external glucose induce mitochondrial stress, as revealed by the accumulation of reactive oxygen species (ROS) and the activation of the ROS-sensitive checkpoint, p38␣. In contrast, loss of function of Lrp6 reduces Wnt responsiveness but has little impact on growth. This highlights the distinct functions of these two Lrp receptors and an important Wnt ligand-independent role of Lrp5 in glucose uptake in mammary epithelial cells.A ll somatic stem cells tested to date rely on Wnt signaling to maintain their pluripotentiality (1). From the point of view of regenerative medicine, this requirement has some disadvantages, since Wnt signaling can also be highly oncogenic (2). If the molecular regulation of Wnt signaling is better understood, it may be possible to tease apart the positive and negative aspects of the pathway.Our study focuses on the signals generated at the cell surface by the Lrp5 (low-density lipoprotein receptor-related protein 5) and Lrp6 Wnt signaling receptors. Cell surface presentation of Lrp species is considered to be the limiting factor for Wnt signal generation (3). Mammary epithelial cells in vitro and in vivo grow and divide in response to ectopic Wnt signals. Thus, overexpression of Wnt1 or Wnt10B in mouse mammary glands leads to ductal hyperplasia, inducing cell division in both luminal and basal cells that together comprise the mammary ducts (4). Basal stem cells accumulate as a fraction of the total population (5), and solitary adenocarcinomas arise with a median latency of 7 months, comprising both mammary epithelial cell lineages (6). Thus, as for intestinal cell populations (2), Wnt signaling is a robust growth signal for mammary epithelial cells and acts as an oncogenic stimulus with a relatively low efficiency.We previously showed that Lrp5 is required to sustain the basal stem cell activity in mammary glands, and also for breast tumor development in response to Wnt1 (5,7,8). This was a surprising result, since Lrp5 and Lrp6 are coexpressed by basal mammary epithelial cells and because Lrp6 is known to be a more effective transducer of Wnt ligand activation (9, 10). Lrp5 and Lrp6 share 73% and 64% protein sequence identity in their extracellular and intracellular domains, respectively (11).Almost all the information we know a...

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