Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling

Sandilands, Emma; Serrels, Bryan; McEwan, David G.; Morton, Jennifer P.; Macagno, Juan Pablo; McLeod, Kenneth J.; Stevens, Craig; Brunton, Valerie G.; Langdon, Wallace Y.; Vidal, Marcos; Sansom, Owen J.; Đikić, Ivan; Wilkinson, Simon; Frame, Margaret C.

doi:10.1038/ncb2386

Cited by 162 publications

(201 citation statements)

References 22 publications

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“…Taking these data together, we feel that future studies should clarify the molecular basis behind these observations. Present findings are consistent with an earlier report by Sandilands et al that Cbl is required for autophagic targeting of active c-Src in squamouse carcinoma cells (36), providing a confirmatory evidence that a similar molecular pathway is operational in normal epithelial cells. Because of technical challenges associated with manipulating primary cells, we have yet to investigate whether this function requires ubiquitin ligase activity of Cbl family proteins.…”

Section: Discussionsupporting

confidence: 94%

“…Sandilands et al previously reported that Cbl functions as a selective autophagy cargo receptor to protect FAK-deficient mouse squamous carcinoma cells from cell death caused by active Src turnover failure (36). Although their system differs from our present model in a number of aspects, colocalization of ProteoStat (+) aggregates with an autophagosome marker LC3, as well as the presence of active c-Src in detergent-insoluble fractions in our system, led us to ask whether the death of Cbl triple-deficient MECs was because of accumulation of active c-Src.…”

Section: Dasatinib Blocks Protein Aggregate Formation and Restores Ormentioning

confidence: 99%

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Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation

Mukhopadhyay

Triplett

Bargar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Casitas B-cell lymphoma (Cbl) family ubiquitin ligases negatively regulate tyrosine kinase-dependent signal transduction by promoting degradation of active kinases. We and others previously reported that loss of Cbl functions caused hyperproliferation in lymphoid and hematopoietic systems. Unexpectedly, Cbl deletion in Cbl-b-null, Cbl-c-null primary mouse mammary epithelial cells (MECs) (Cbl triple-deficiency) induced rapid cell death despite enhanced MAP kinase and AKT activation. Acute Cbl triple-deficiency elicited distinct transcriptional and biochemical responses with partial overlap with previously described cellular reactions to unfolded proteins and oxidative stress. Although the levels of reactive oxygen species were comparable, detergent-insoluble protein aggregates containing phosphorylated c-Src accumulated in Cbl triple-deficient MECs. Treatment with a broad-spectrum kinase inhibitor dasatinib blocked protein aggregate accumulation and restored in vitro organoid formation. This effect is most likely mediated through c-Src because Cbl triple-deficient MECs were able to form organoids upon shRNA-mediated c-Src knockdown. Taking these data together, the present study demonstrates that Cbl family proteins are required to protect MECs from proteotoxic stress-induced cell death by promoting turnover of active c-Src.CBL | ubiquitin ligase | tyrosine kinase | protein degradation | stress response

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Section: Discussionsupporting

confidence: 94%

Section: Dasatinib Blocks Protein Aggregate Formation and Restores Ormentioning

confidence: 99%

Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation

Mukhopadhyay

Triplett

Bargar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, our work also emphasizes how FAK signaling can exert contrasting effects on autophagy and cell survival. Recent work from Sandilands and colleagues using a skin cancer model demonstrated that components of the autophagy pathway are intimately associated with focal adhesions, and that loss of FAK can trigger an apoptotic response, unless the active Src released upon FAK ablation is subject to autophagic targeting (49). This led to the suggestion that combining FAK and/or Src inhibitors with an autophagy inhibitor may reduce the viability of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

Lee

Hochgräfe

Lin

et al. 2014

Molecular Cancer Therapeutics

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Docetaxel remains the standard-of-care for men diagnosed with metastatic castrate-resistant prostate cancer (CRPC). However, only approximately 50% of patients benefit from treatment and all develop docetaxelresistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with docetaxel resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry-based phosphoproteomics, we identified that metastatic docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison with parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein-protein interaction networks related to these pathways in docetaxel-resistant cells. Treatment with the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, whereas cotreatment with PF-00562271 and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of cotreatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where coadministration with docetaxel may be used in patients with CRPC to overcome chemoresistance. Mol Cancer Ther; 13(1); 190-201. Ó2013 AACR.

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“…For instance, Cbl has been identified as an autophagy receptor for the active, nonreceptor, membrane-associated tyrosine kinase Src (Sandilands et al, 2012). Increased Src activity promotes tumorigenesis but excessive Src signaling can be cytotoxic (Yeatman, 2004).…”

Section: Specialized Autophagy Receptorsmentioning

confidence: 99%

The LIR motif – crucial for selective autophagy

Birgisdottir

Lamark

Johansen

2013

Journal of Cell Science

769

492

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Summary(Macro)autophagy is a fundamental degradation process for macromolecules and organelles of vital importance for cell and tissue homeostasis. Autophagy research has gained a strong momentum in recent years because of its relevance to cancer, neurodegenerative diseases, muscular dystrophy, lipid storage disorders, development, ageing and innate immunity. Autophagy has traditionally been thought of as a bulk degradation process that is mobilized upon nutritional starvation to replenish the cell with building blocks and keep up with the energy demand. This view has recently changed dramatically following an array of papers describing various forms of selective autophagy. A main driving force has been the discovery of specific autophagy receptors that sequester cargo into forming autophagosomes (phagophores). At the heart of this selectivity lies the LC3-interacting region (LIR) motif, which ensures the targeting of autophagy receptors to LC3 (or other ATG8 family proteins) anchored in the phagophore membrane. LIR-containing proteins include cargo receptors, members of the basal autophagy apparatus, proteins associated with vesicles and of their transport, Rab GTPaseactivating proteins (GAPs) and specific signaling proteins that are degraded by selective autophagy. Here, we comment on these new insights and focus on the interactions of LIR-containing proteins with members of the ATG8 protein family.

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Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling

Cited by 162 publications

References 22 publications

Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation

Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

The LIR motif – crucial for selective autophagy

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