Abl Kinases Regulate Autophagy by Promoting the Trafficking and Function of Lysosomal Components

Yogalingam, Gouri; Pendergast, Ann Marie

doi:10.1074/jbc.m804543200

Cited by 97 publications

(98 citation statements)

References 47 publications

(60 reference statements)

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“…It is possible that c-Abl kinase could regulate this Rab either directly or through modification of a GTPase-activating protein of the guanine nucleotide exchange factor. Second, c-Abl has been shown to promote the autophagic process indirectly though activation of lysosome motility and capacity of lysosomes to degrade substrate (37). How imatinib facilitates TfR1-Hsc70 interaction and trafficking to the lysosome for degradation is unclear.…”

Section: Discussionmentioning

confidence: 99%

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Cao

Schroeder

Chen

et al. 2016

Journal of Biological Chemistry

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Clathrin-mediated endocytosis of transferrin (Tf) and its cognate receptor (TfR1) is a central pathway supporting the uptake of trophic iron. It has generally been assumed that this is a constitutive process. However, we have reported that the non-receptor tyrosine kinase, Src, is activated by Tf to facilitate the internalization of the Tf-TfR1 ligand-receptor complex. As an extension of these findings, we have tested whether subsequent trafficking steps might be regulated by additional kinase-dependent cascades, and we observed a significant endocytic block by inhibiting c-Abl kinase by a variety of methods. Importantly, Tf internalization was reduced significantly in all of these cell models and could be restored by re-expression of WT c-Abl. Surprisingly, this attenuated Tf-TfR1 endocytosis was due to a substantial drop in both the surface and total cellular receptor levels. Additional studies with the LDL receptor showed a similar effect. Surprisingly, immunofluorescence microscopy of imatinib-treated cells revealed a marked colocalization of internalized TfR1 with late endosomes/lysosomes, whereas attenuating the lysosome function with several inhibitors reduced this receptor loss. Importantly, inhibition of c-Abl resulted in a striking redistribution of the chaperone Hsc70 from a diffuse cytosolic localization to an association with the TfR1 at the late endosome-lysosome. Pharmacological inhibition of Hsc70 ATPase activity in cultured cells by the drug VER155008 prevents this chaperone-receptor interaction, resulting in an accumulation of the TfR1 in the early endosome. Thus, inhibition of c-Abl minimizes receptor recycling pathways and results in chaperone-dependent trafficking of the TfR1 to the lysosome for degradation. These findings implicate a novel role for c-Abl and Hsc70 as an unexpected regulator of Hsc70-mediated transport of trophic receptor cargo between the early and late endosomal compartments.

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Section: Discussionmentioning

confidence: 99%

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Cao

Schroeder

Chen

et al. 2016

Journal of Biological Chemistry

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“…Abl kinases have been shown to regulate organelle trafficking by promoting fusion of autophagosomes to lysosomes, and regulating lysosome motility and localization in fibroblasts and alveolar carcinoma cells (Yogalingam and Pendergast, 2008). Abl kinases also promote endosome maturation and trafficking of proteins to the lysosome for degradation (Fiore et al, 2014;Yogalingam and Pendergast, 2008).…”

Section: Abl-dependent Regulation Of Membrane and Organelle Traffickingmentioning

confidence: 99%

“…Abl kinases also promote endosome maturation and trafficking of proteins to the lysosome for degradation (Fiore et al, 2014;Yogalingam and Pendergast, 2008). Trafficking of early endosomes and lysosomes along microtubules facilitates organelle motility and fusion events.…”

Section: Abl-dependent Regulation Of Membrane and Organelle Traffickingmentioning

confidence: 99%

Multifunctional Abl kinases in health and disease

Khatri

Wang

Pendergast

2016

Journal of Cell Science

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115

145

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The Abelson tyrosine kinases were initially identified as drivers of leukemia in mice and humans. The Abl family kinases Abl1 and Abl2 regulate diverse cellular processes during development and normal homeostasis, and their functions are subverted during inflammation, cancer and other pathologies. Abl kinases can be activated by multiple stimuli leading to cytoskeletal reorganization required for cell morphogenesis, motility, adhesion and polarity. Depending on the cellular context, Abl kinases regulate cell survival and proliferation. Emerging data support important roles for Abl kinases in pathologies linked to inflammation. Among these are neurodegenerative diseases and inflammatory pathologies. Unexpectedly, Abl kinases have also been identified as important players in mammalian host cells during microbial pathogenesis. Thus, the use of Abl kinase inhibitors might prove to be effective in the treatment of pathologies beyond leukemia and solid tumors. In this Cell Science at a Glance article and in the accompanying poster, we highlight the emerging roles of Abl kinases in the regulation of cellular processes in normal cells and diverse pathologies ranging from cancer to microbial pathogenesis.

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“…Like acidification defects in the endo/lysosomal compartment, defects in the transport or expression of lysosomal enzymes induce a blockade of autophagy, which is characterized by an accumulation of autophagic vacuoles [93,94]. The final stage of autophagy is the efflux of metabolites generated by the lysosomal degradation of macromolecules into the cytosol (reviewed in [95]).…”

Section: Acidification and Degradationmentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

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Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

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Abl Kinases Regulate Autophagy by Promoting the Trafficking and Function of Lysosomal Components

Cited by 97 publications

References 47 publications

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

Multifunctional Abl kinases in health and disease

Overview of macroautophagy regulation in mammalian cells

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