JAK2-Mediated Phosphorylation of Stress-Induced Phosphoprotein-1 (STIP1) in Human Cells

Int J Mol Sci. 2022 Feb 22;23(5):2420. doi: 10.3390/ijms23052420.


Stress-induced phosphoprotein-1 (STIP1)-a heat shock protein (HSP)70/HSP90 adaptor protein-is commonly overexpressed in malignant cells, where it controls proliferation via multiple signaling pathways, including JAK2/STAT3. We have previously shown that STIP1 stabilizes the protein tyrosine kinase JAK2 in cancer cells via HSP90 binding. In this study, we demonstrate that STIP1 may act as a substrate for JAK2 and that phosphorylation of tyrosine residues 134 and 152 promoted STIP1 protein stability, induced its nuclear-cytoplasmic shuttling, and promoted its secretion into the extracellular space. We also found that JAK2-mediated STIP1 phosphorylation enhanced cell viability and increased resistance to cisplatin-induced cell death. Conversely, interference STIP1 with JAK2 interaction-attained either through site-directed mutagenesis or the use of cell-penetrating peptides-decreased JAK2 protein levels, ultimately leading to cell death. On analyzing human ovarian cancer specimens, JAK2 and STIP1 expression levels were found to be positively correlated with each other. Collectively, these results indicate that JAK2-mediated phosphorylation of STIP-1 is critical for sustaining the JAK2/STAT3 signaling pathway in cancer cells.

Keywords: JAK2/STAT3 signaling; STIP1; cancer; phosphorylation.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Janus Kinase 2 / genetics*
  • Janus Kinase 2 / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Phosphorylation
  • Protein Stability
  • Protein Transport
  • Signal Transduction


  • Biomarkers, Tumor
  • Heat-Shock Proteins
  • STIP1 protein, human
  • JAK2 protein, human
  • Janus Kinase 2
  • Cisplatin