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

Chandrani Mukhopadhyay, Aleata Triplett, Tom Bargar, Carol Heckman, Kay Uwe Wagner, Mayumi Naramura

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E8228-E8237
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number51
DOIs
StatePublished - Dec 20 2016

Fingerprint

B-Cell Lymphoma
Breast
Epithelial Cells
Proteins
Organoids
Phosphotransferases
Cell Death
Hematopoietic System
Protein Unfolding
Ligases
Ubiquitin
Detergents
Protein-Tyrosine Kinases
Small Interfering RNA
Reactive Oxygen Species
Signal Transduction
Oxidative Stress

Keywords

  • CBL
  • Protein degradation
  • Stress response
  • Tyrosine kinase
  • Ubiquitin ligase

ASJC Scopus subject areas

  • General

Cite this

Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation. / Mukhopadhyay, Chandrani; Triplett, Aleata; Bargar, Tom; Heckman, Carol; Wagner, Kay Uwe; Naramura, Mayumi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 51, 20.12.2016, p. E8228-E8237.

Research output: Contribution to journalArticle

Mukhopadhyay, Chandrani ; Triplett, Aleata ; Bargar, Tom ; Heckman, Carol ; Wagner, Kay Uwe ; Naramura, Mayumi. / Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 51. pp. E8228-E8237.
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