Interactions of EGFR and caveolin-1 in human glioblastoma cells: evidence that tyrosine phosphorylation regulates EGFR association with caveolae

Abulrob, Abedelnasser; Giuseppin, Sabina; Andrade, Moises F.; McDermid, Angela; Moreno, María; Stanimirovic, Danica

doi:10.1038/sj.onc.1207911

Cited by 122 publications

(134 citation statements)

References 42 publications

(48 reference statements)

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“…The constitutive TK activity of the EGFRvIII results in the malignant transformation of cells (Han et al, 1996;Nagane et al, 1996;Huang et al, 1997;Antonyak et al, 1998;Montgomery, 2002;Johns et al, 2003;Abulrob et al, 2004;Luwor et al, 2004;Pedersen et al, 2004). In this study, we found that the EGFRvIII is regulated by the Cbl proteins in an identical manner to the WT EGFR.…”

Section: Discussionsupporting

confidence: 59%

“…Unlike the wild-type (WT) EGFR, the EGFRvIII is unable to bind to EGF or transforming growth factor-α (Ekstrand et al, 1994;Nishikawa et al, 1994;Moscatello et al, 1996) but, instead, it can dimerize spontaneously (Moscatello et al, 1996;Fernandes et al, 2001;Montgomery, 2002). The spontaneous dimerization and ensuing TK activation of the EGFRvIII is necessary to transform cells (Han et al, 1996;Nagane et al, 1996;Huang et al, 1997;Antonyak et al, 1998;O'Rourke et al, 1998;Montgomery, 2002;Johns et al, 2003;Abulrob et al, 2004;Luwor et al, 2004;Pedersen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

et al. 2006

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The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The over-expression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFR-vIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

et al. 2006

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“…Caveolin-1 has a scaffolding domain within its NH2-terminal region. Through this domain, caveolin-1 interacts with G-protein -subunits, HRas, Src-family tyrosine kinases, PKC isoforms, EGF-R, Neu, and eNOS and regulates their activities (Razani and Lisanti, 2001;Abulrob et al, 2004;Cao et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle

Kim²,

Ryu³

et al. 2007

Exp Mol Med

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It is well known that exercise can have beneficial effects on insulin resistance by activation of glucose transporter. Following up our previous report that caveolin-1 plays an important role in glucose uptake in L6 skeletal muscle cells, we examined whether exercise alters the expression of caveolin-1, and whether exercise-caused changes are muscle fiber and exercise type specific. Fifity week-old Sprague Dawley (SD) rats were trained to climb a ladder and treadmill for 8 weeks and their soleus muscles (SOL) and extensor digitorum longus muscles (EDL) were removed after the last bout of exercise and compared with those from non-exercised animals. We found that the expression of insulin related proteins and caveolins did not change in SOL muscles after exercise. However, in EDL muscles, the expression of insulin receptor β (IRβ) and glucose transporter-4 (GLUT-4) as well as phosphorylation of AKT and AMPK increased with resistance exercise but not with aerobic exercise. Also, caveolin-1 and caveolin-3 increased along with insulin related proteins only in EDL muscles by resistance exercise. These results suggest that upregulation of caveolin-1 in the skeletal muscle is fiber specific and exercise type specific, implicating the requirement of the specific mode of exercise to improve insulin sensitivity.

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“…A caveolin binding motif within the kinase domain of the EGF receptor mediates the interaction of EGF receptor with caveolin-1 (56,57). In human glioblastoma cell lines, EGF receptor rapidly moves out of caveolae domains in response to EGF and then internalizes and degrades via a clathrin-dependent endocytic pathway (56,58,59). In our studies we detected co-localization and biochemical association between the EGF receptor, integrin ␣2, and caveolin-1 without EGF treatment.…”

Section: Activated Egf Receptor Initiates Transient Internalization Ofmentioning

confidence: 99%

“…Recent studies (55,56) have shown that a variety of cell surface receptors, including the EGF receptor, are present in caveolae and lipid rafts. A caveolin binding motif within the kinase domain of the EGF receptor mediates the interaction of EGF receptor with caveolin-1 (56,57).…”

Section: Activated Egf Receptor Initiates Transient Internalization Ofmentioning

confidence: 99%

Activated Epidermal Growth Factor Receptor Induces Integrin α2 Internalization via Caveolae/Raft-dependent Endocytic Pathway

Ning¹,

Buranda

Hudson³

2007

Journal of Biological Chemistry

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Elevated expression or activity of the epidermal growth factor (EGF) receptor is common in ovarian cancer and is associated with poor patient prognosis. Our previous studies demonstrated that expression of the constitutively active mutant form of the EGF receptor (EGFRvIII) in ovarian cancer cells led to reduction in integrin ␣2 surface expression, defects in cell spreading, and disruption of focal adhesions. Inhibition of EGFRvIII catalytic activity reversed the response, suggesting that EGF receptor activation regulates integrin ␣2. In this study we found that EGF treatment resulted in a transient loss of integrin ␣2 from the cell surface. Before EGF stimulation, integrin ␣2 and EGF receptors were associated based on biochemical and immuno-colocalization approaches. After EGF treatment, EGF receptor and integrin ␣2 were internalized and segregated into different compartments. Integrin ␣2, but not EGF receptor, was associated with caveolin-1 and GM1 (Gal_1,3GalNAc_1,4(Neu5Ac-_ 2,3)Gal_1,4Glc_1,1-ceramide) gangliosides, suggesting caveolae-mediated endocytosis. Moreover, integrin ␣2 was subsequently targeted to the Golgi apparatus and the endoplasmic reticulum. Together, these findings demonstrate that activated EGF receptor transiently modulates integrin ␣2 cell surface expression and stimulates integrin ␣2 trafficking via caveolae/ raft-mediated endocytosis, representing a novel mechanism by which the EGF receptor may regulate integrin-mediated cell behavior.Epithelial ovarian carcinoma accounts for 80 -90% of ovarian tumors and is the leading cause of death from gynecologic malignancy, resulting in 16,210 deaths in 2005 (1). Because of the current inability to detect disease confined to the ovary (stage I), ϳ75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of Ͻ20%, whereas patients diagnosed with cancer localized to the ovary have a Ͼ90% 5-year survival. Clinically, tumors often involve the ovary and omentum, with diffuse intraperitoneal metastases and malignant ascites. Ovarian cancer metastasis results from numerous intraperitoneal adhesive events, suggesting that carcinoma cell integrins regulate subsequent invasive or metastatic behavior (2-4).Integrins are the major family of cell surface receptors that mediate attachment to the extracellular matrix, and these integrin-mediated adhesive interactions are intimately involved in the regulation of many cellular functions, including tumor cell growth, apoptosis, and metastasis (5-7). After disseminated primary ovarian tumor cells attach to the peritoneal mesothelial monolayer via CD44 (8 -10), integrin-mediated cell-matrix interaction potentiates intraperitoneal invasion. Ovarian carcinoma cells extend cytoplasmic processes through the junctional margins of neighboring mesothelial cells, inducing cellular retraction and exposure of the submesothelial extracellular matrix, followed by integrin-mediated adhesion to the newly exposed matrix (11,12). Analysis of adhesive preferences and integ...

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Interactions of EGFR and caveolin-1 in human glioblastoma cells: evidence that tyrosine phosphorylation regulates EGFR association with caveolae

Cited by 122 publications

References 42 publications

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle

Activated Epidermal Growth Factor Receptor Induces Integrin α2 Internalization via Caveolae/Raft-dependent Endocytic Pathway

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