Bag1-Hsp 70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth

Jaewhan Song, Masahiro Takeda, Richard I. Morimoto

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

Survival after stress requires the precise orchestration of cell-signalling events to ensure that biosynthetic processes are alerted and cell survival pathways are initiated. Here we show that Bag1, a co-chaperone for heat-shock protein 70 (Hsp70), coordinates signals for cell growth in response to cell stress, by downregulating the activity of Raf-1 kinase. Raf-1 and Hsp70 compete for binding to Bag1, such that Bag1 binds to and activates Raf-1, subsequently activating the downstream extracellular signal-related kinases (ERKs). When levels of Hsp70 are elevated after heat shock, or in cells conditionally overexpressing Hsp70, Bag1-Raf-1 is displaced by Bag1-Hsp70, and DNA synthesis is arrested. Mutants Bag1C204A and Bag1E208A, which cannot bind Hsp70, constitutively activate Raf-1/ERK kinases but are unaffected by Hsp70; consequently neither Bag1-Raf-1 nor DNA synthesis is negatively affected during heat shock. Likewise, Hsp70F245S, Hsp70R262W and Hsp70L282R, which retain chaperone activity but do not bind to Bag1, fail to repress Bag1 activation of Raf-1/ERK kinase. We propose that Bag1 functions in the heat-shock response to coordinate cell growth signals and mitogenesis, and that Hsp70 functions as a sensor in stress signalling.

Original languageEnglish
Pages (from-to)276-282
Number of pages7
JournalNature Cell Biology
Volume3
Issue number3
DOIs
Publication statusPublished - 2001 Mar 20

Fingerprint

Physiological Stress
HSP70 Heat-Shock Proteins
Phosphotransferases
Growth
Shock
Hot Temperature
Proto-Oncogene Proteins c-raf
Heat-Shock Response
DNA
Cell Survival
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

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abstract = "Survival after stress requires the precise orchestration of cell-signalling events to ensure that biosynthetic processes are alerted and cell survival pathways are initiated. Here we show that Bag1, a co-chaperone for heat-shock protein 70 (Hsp70), coordinates signals for cell growth in response to cell stress, by downregulating the activity of Raf-1 kinase. Raf-1 and Hsp70 compete for binding to Bag1, such that Bag1 binds to and activates Raf-1, subsequently activating the downstream extracellular signal-related kinases (ERKs). When levels of Hsp70 are elevated after heat shock, or in cells conditionally overexpressing Hsp70, Bag1-Raf-1 is displaced by Bag1-Hsp70, and DNA synthesis is arrested. Mutants Bag1C204A and Bag1E208A, which cannot bind Hsp70, constitutively activate Raf-1/ERK kinases but are unaffected by Hsp70; consequently neither Bag1-Raf-1 nor DNA synthesis is negatively affected during heat shock. Likewise, Hsp70F245S, Hsp70R262W and Hsp70L282R, which retain chaperone activity but do not bind to Bag1, fail to repress Bag1 activation of Raf-1/ERK kinase. We propose that Bag1 functions in the heat-shock response to coordinate cell growth signals and mitogenesis, and that Hsp70 functions as a sensor in stress signalling.",
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Bag1-Hsp 70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth. / Song, Jaewhan; Takeda, Masahiro; Morimoto, Richard I.

In: Nature Cell Biology, Vol. 3, No. 3, 20.03.2001, p. 276-282.

Research output: Contribution to journalArticle

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