Stress-induced phosphoprotein 1 (STIP1)

Stress-induced phosphoprotein 1 (STIP1) is an evolutionarily conserved co-chaperone that orchestrates the transfer and functional modulation between heat shock proteins Hsp70 and Hsp90 during protein folding, client protein maturation, and assembly[1][2][3][6]. STIP1 contains multiple tetratricopeptide repeat (TPR) domains enabling specific recognition and interaction with the C-terminal EEVD motifs on Hsp70 and Hsp90; it also modulates chaperone activity by stimulating Hsp70 ATPase activity while inhibiting Hsp90’s ATPase cycle, thereby regulating the proteostasis network[1][2]. Beyond the central chaperone machinery, STIP1 acts as a scaffold for the assembly of signaling complexes, notably interfacing with GSK3β and LSD1 to promote phosphorylation-dependent oncogenic signaling and cell proliferation[3]. STIP1 is frequently overexpressed and secreted in a range of solid tumors, driving pathways including ERK, PI3K–AKT, JAK2–STAT3, and Wnt/β–catenin, and also functions as a prognostic biomarker and potential therapeutic target[2][3]. Additional roles include modulation of nuclear architecture (via emerin), participation in angiogenesis, autoimmune and inflammatory disease involvement as an autoantigen, and genetic susceptibility loci for developmental disorders such as biliary atresia and asthma[2]. Pharmacological inhibition of STIP1-associated complexes, using drugs like LSD1 and GSK3β inhibitors, exhibits synergistic anticancer effects, though the essential developmental function positions STIP1 as a challenging therapeutic target[3].

Other names

HopHOPSTI1STI1LHsc70/Hsp90-organizing proteinRenal carcinoma antigen NY-REN-11Transformation-sensitive protein IEF SSP 3521HEL-S-94nP60NY-REN-11 antigenEpididymis secretory sperm binding protein Li 94n

Inhibition or disruption of STIP1–Hsp90 complex affects client protein stability (e.g. LSD1). Synergistic cell death induction by dual targeting LSD1 and GSK3β (coordinated via STIP1). Inhibition of chaperone cycle and downstream oncogenic signaling pathways.