Abstract
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.
Highlights
Stress-induced phosphoprotein 1 (STIP1, Gene ID:10963)—an adaptor protein of the HSP70/HSP90 chaperone heterocomplex [1,2]—contains a nuclear localization signal regulated by cell cycle kinase phosphorylation [3] and plays a critical role in cell proliferation [4]
As JAK2-mediated phosphorylation of STIP-1 was found to be critical for sustaining the JAK2/STAT3 signaling pathway in malignant cells, blockading of Stress-induced phosphoprotein-1 (STIP1) phosphorylation by JAK2 provides an avenue for developing novel potential anticancer strategies
Our results indicate that JAK2 is capable of phosphorylating STIP1 on tyrosine residues at position 134 and 152—an event which plays a critical role in maintaining the JAK2/STAT3 signaling pathway
Summary
Stress-induced phosphoprotein 1 (STIP1, Gene ID:10963)—an adaptor protein of the HSP70/HSP90 chaperone heterocomplex [1,2]—contains a nuclear localization signal regulated by cell cycle kinase phosphorylation [3] and plays a critical role in cell proliferation [4]. Significant increases in the expression of STIP1 have been reported in several solid tumors, including hepatocellular carcinoma [5], pancreatic cancer [6], ovarian cancer [7,8], colon cancer [9], breast cancer [10], and cholangiocellular carcinoma [11]. Targeted downregulation of endogenous STIP1 expression resulted in a decreased proliferation of pancreatic cancer, ovarian cancer, and osteosarcoma cells [12–15]. There is evidence that STIP1 may act as a secretory protein to promote tumor progression. In this regard, increased STIP1 serum levels in patients with ovarian cancer and hepatocellular carcinoma have been shown to activate the ERK2, SMAD1/5, and PI3K-AKT signaling pathways [8,17,18]
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