Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src@

Chung, Byung Min; Raja, Srikumar M.; Clubb, Robert J.; Tu, Chun; George, Manju; Band, Vimla; Band, Hamid

doi:10.1186/1471-2121-10-84

Cited by 84 publications

(102 citation statements)

References 72 publications

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“…This is the first examination of the relationship between SPRY2 and EGFR expression on EGFR recycling in NSCLC cells. Although it was previously reported that mutant EGFR colocalized with transferrin (Chung et al, 2009), suggesting that mutant EGFR is preferentially recycled, our measurements are the first quantitative comparison of recycling between wild-type and mutant EGFR, as far as we are aware. We found that mutant EGFR was almost entirely sorted for recycling (f r .0.9), whereas wild-type EGFR was split more evenly between degradation and recycling (f r ,0.5).…”

Section: Discussionmentioning

confidence: 80%

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Regulation of EGFR trafficking and cell signaling by Sprouty2 and MIG6 in lung cancer cells

Walsh

Lazzara

2013

Journal of Cell Science

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SummaryThe duration and specificity of epidermal growth factor receptor (EGFR) activation and signaling are determinants of cellular decision processes and are tightly regulated by receptor dephosphorylation, internalization and degradation. In addition, regulatory proteins that are upregulated or activated post-transcriptionally upon receptor activation may initiate feedback loops that play crucial roles in spatiotemporal regulation of signaling. We examined the roles of Sprouty2 (SPRY2) and mitogen-inducible gene 6 (MIG6), two feedback regulators of EGFR trafficking and signaling, in lung cancer cells with or without EGFR-activating mutations. These mutations are of interest because they confer unusual cellular sensitivity to EGFR inhibition through a mechanism involving an impairment of EGFR endocytosis. We found that the endocytosis of wild-type and mutant EGFR was promoted by SPRY2 knockdown and antagonized by MIG6 knockdown. SPRY2 knockdown also significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation, EGFR expression, and EGFR recycling. In a cell line expressing mutant EGFR, this effect on ERK led to a marked increase in cell death response to EGFR inhibition. The effects of SPRY2 knockdown on EGFR endocytosis and recycling were primarily the result of the concomitant change in EGFR expression, but this was not true for the observed changes in ERK phosphorylation. Thus, our study demonstrates that SPRY2 and MIG6 are important regulators of wild-type and mutant EGFR trafficking and points to an EGFR expression-independent function of SPRY2 in the regulation of ERK activity that may impact cellular sensitivity to EGFR inhibitors, especially in the context of EGFR mutation.

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Section: Discussionmentioning

confidence: 80%

“…6B). It has been suggested previously, based on receptor localization, that mutant EGFR is preferentially recycled (Chung et al, 2009). However, enhanced recycling of mutant EGFR has never been quantified, as far as we are aware.…”

Section: Spry2 Controls Egfr Sorting In An Egfr-expressiondependent Mmentioning

confidence: 99%

Regulation of EGFR trafficking and cell signaling by Sprouty2 and MIG6 in lung cancer cells

Walsh

Lazzara

2013

Journal of Cell Science

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“…While we investigated one EGFR phosphorylation site, other sites, such as Tyr 845 , may be involved in the EGFR-Src interaction (16). Interestingly, the interaction of mutated EGFR in cancer with Src is different from the interaction of normal EGFR with Src (14), which may account for the longer time required for Src activation in our EGFR-mutant cell line (Fig. 3).…”

Section: Discussionmentioning

confidence: 98%

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Dossa

Escobar

Golden

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

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“…We have shown that c-Src interacts with oncogenic EGFR mutants in non-small cell lung cancer cells in the ERC, an interaction required for mutant EGFR-mediated oncogenic transformation (112,113). Src has been shown to be a component of the pericentrion (67), suggesting that ErbB2 may signal in collaboration with Src in the ERC.…”

Section: Discussionmentioning

confidence: 99%

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

Bailey

Luan

Tom

et al. 2014

Journal of Biological Chemistry

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ErbB2 overexpression drives oncogenesis in 20–30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca2+-dependent PKCs (α, β1, βII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.

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Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src@

Cited by 84 publications

References 72 publications

Regulation of EGFR trafficking and cell signaling by Sprouty2 and MIG6 in lung cancer cells

Regulation of EGFR trafficking and cell signaling by Sprouty2 and MIG6 in lung cancer cells

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

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