ERK-dependent phosphorylation of the linker and substrate-binding domain of HSP70 increases folding activity and cell proliferation

Semi Lim, Dae Gyu Kim, Sunghoon Kim

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


The enhanced productive folding of translated polypeptides by heat shock protein 70 (HSP70) is often required for the survival of cancer cells. Although the folding activity of HSP70 is considered a significant determinant of the progression of cancer cells, it is still unknown how this activity could be regulated. Here, we report that the phosphorylation of HSP70 facilitates its folding activity, enhancing cell proliferation. Mass spectrometry identified the serine residues at positions 385 and 400 in the linker and substrate-binding domains of HSP70, respectively, as sites of phosphorylation mediated by EGF signaling, and this result was further confirmed by site-directed mutagenesis. ERK is known to be a specific kinase. The phosphorylation of the two sites induces the extended conformation of HSP70 via the regulation of the binding of the linker to the nucleotide- and substrate-binding domains, augmenting the binding affinity of HSP70 to substrates and enhancing its folding activity; this ultimately results in pro-proliferative effects. Cell lines harboring activated ERK showed increased phosphorylation of HSP70, and a positive correlation between the phosphorylation of HSP70 and the activity of ERK was observed. Thus, this study demonstrated that the ERK-dependent phosphorylation of HSP70 facilitated its folding activity and cellular proliferative function.

Original languageEnglish
Article number112
JournalExperimental and Molecular Medicine
Issue number9
Publication statusPublished - 2019 Sept 1

Bibliographical note

Funding Information:
This work was supported by a Global Frontier Project grant (NRF-M3A6A4–2010–0029785) from the National Research Foundation funded by the Ministry of Science and ICT (MSIT) of Korea.

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


Dive into the research topics of 'ERK-dependent phosphorylation of the linker and substrate-binding domain of HSP70 increases folding activity and cell proliferation'. Together they form a unique fingerprint.

Cite this