Cholesterol Depletion from the Plasma Membrane Triggers Ligand-independent Activation of the Epidermal Growth Factor Receptor

Chen, Xu; Resh, Marilyn D.

doi:10.1074/jbc.m208327200

Cited by 172 publications

(169 citation statements)

References 59 publications

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“…Lipid raft -destabilizing agents, such as MBCD and filipin, are known to phosphorylate EGFR in cells (44)(45)(46). Interestingly, MBCD treatment with PC-3 cells inhibited basal and CXCL12-induced HER2 phosphorylation in lipid rafts.…”

Section: Discussionmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

116

102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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Section: Discussionmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

116

102

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“…First, it has not been easy to understand why cholesterol depletion and chilling could both activate mitogen-activated protein kinase signaling (Furuchi and Anderson, 1998;Kabouridis et al, 2000;Chen and Resh, 2002;Gousset et al, 2002;Magee et al, 2005), because the two manipulations are thought to exert opposite effects on rafts, but the present result on GM1 suggests that the two manipulations may affect the distribution of individual raft-philic molecules in the same manner and could cause a similar outcome. This tenet may be tested directly by probing fine distribution of signaling proteins that reside in the inner leaflet of the cell membrane.…”

Section: Gm1 Clustering In the Cell Membranementioning

confidence: 90%

Gangliosides GM1 and GM3 in the Living Cell Membrane Form Clusters Susceptible to Cholesterol Depletion and Chilling

Fujita¹,

Cheng²,

Hirakawa

et al. 2007

MBoC

217

173

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Presence of microdomains has been postulated in the cell membrane, but two-dimensional distribution of lipid molecules has been difficult to determine in the submicrometer scale. In the present paper, we examined the distribution of gangliosides GM1 and GM3, putative raft molecules in the cell membrane, by immunoelectron microscopy using quick-frozen and freeze-fractured specimens. This method physically immobilized molecules in situ and thus minimized the possibility of artifactual perturbation. By point pattern analysis of immunogold labeling, GM1 was shown to make clusters of <100 nm in diameter in normal mouse fibroblasts. GM1-null fibroblasts were not labeled, but developed a similar clustered pattern when GM1 was administered. On cholesterol depletion or chilling, the clustering of both endogenous and exogenously-loaded GM1 decreased significantly, but the distribution showed marked regional heterogeneity in the cells. GM3 also showed cholesterol-dependent clustering, and although clusters of GM1 and GM3 were found to occasionally coincide, these aggregates were separated in most cases, suggesting the presence of heterogeneous microdomains. The present method enabled to capture the molecular distribution of lipids in the cell membrane, and demonstrated that GM1 and GM3 form clusters that are susceptible to cholesterol depletion and chilling. INTRODUCTIONMicrodomains enriched with cholesterol and sphingolipids, or rafts, have been postulated to exist in the cell membrane (Simons and Ikonen, 1997). Domains showing a liquid-ordered state have been visualized in model membranes (Korlach et al., 1999;Dietrich et al., 2001a), but whether similar domains exist in the biological membranes of living cells, and what their basic properties would be, including size, life span and dynamics, are still under debate (Simons and Ikonen, 1997;Edidin, 2003;Munro, 2003;Kusumi et al., 2004;Mayor and Rao, 2004;Mukherjee and Maxfield, 2004). Recent results, obtained by single-particle tracking and fluorescent resonance energy transfer experiments, have suggested that rafts in normal unstimulated cells are extremely small and may last for Ͻ1 ms (Kenworthy et al., 2004;Kusumi et al., 2004;Sharma et al., 2004). Detergent-resistant membranes have often been regarded as an in vitro correlate of rafts, but detergents themselves have been found to cause domain formation artificially (Heerklotz, 2002). These results have thus posed questions regarding the true existence of rafts in living, nonstimulated cells. In addition, although microscopic identification of rafts has been attempted in a number of studies, putative raft molecules generally show diffuse distribution in the cell membrane without any concentration at the resolution of light microscopy. This result has been interpreted in several different ways, i.e., that rafts do not in fact exist, rafts are too small to be resolved by light microscopy, rafts occupy the majority of the membrane, or rafts do exist but may be disrupted by experimental procedures.GM1 has been generally re...

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“…Despite this, no cholesterol sensor has been proposed for this cell compartment. However, it has been shown that the epidermal growth factor receptor (also known as ErbB1), which resides in the plasma membrane, is phosphorylated after acute cholesterol depletion (8). In turn, ErbB1 phosphorylation causes hyperactivation of the PI3K and the mitogenactivated protein kinase (MAPK) pathways, showing that membrane cholesterol depletion can elicit intracellular signaling cascades (9) and suggesting that some ErbB receptors could be part of a mechanism for sensing plasma membrane cholesterol concentration.…”

mentioning

confidence: 99%

Transcriptional Control of Cholesterol Biosynthesis in Schwann Cells by Axonal Neuregulin 1

Pertusa

Morenilla‐Palao

Carteron

et al. 2007

Journal of Biological Chemistry

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A characteristic feature of many vertebrate axons is their wrapping by a lamellar stack of glially derived membranes known as the myelin sheath. Myelin is a cholesterol-rich membrane that allows for rapid saltatory nerve impulse conduction. Axonal neuregulins instruct glial cells on when and how much myelin they should produce. However, how neuregulin regulates myelin sheath development and thickness is unknown. Here we show that neuregulin receptors are activated by drops in plasma membrane cholesterol, suggesting that they can sense sterol levels. In Schwann cells neuregulin-1 increases the transcription of the 3-hydroxy-3-methylglutarylcoenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. Neuregulin activity is mediated by the phosphatidylinositol 3-kinase pathway and a cAMP-response element located on the reductase promoter. We propose that by activating neuregulin receptors, neurons exploit a cholesterol homeostatic mechanism forcing Schwann cells to produce new membranes for the myelin sheath. We also show that a strong phylogenetic correlation exists between myelination and cholesterol biosynthesis, and we propose that the absence of the sterol branch of the mevalonate pathway in invertebrates precluded the myelination of their nervous system.

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Cholesterol Depletion from the Plasma Membrane Triggers Ligand-independent Activation of the Epidermal Growth Factor Receptor

Cited by 172 publications

References 59 publications

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Gangliosides GM1 and GM3 in the Living Cell Membrane Form Clusters Susceptible to Cholesterol Depletion and Chilling

Transcriptional Control of Cholesterol Biosynthesis in Schwann Cells by Axonal Neuregulin 1

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