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Gene Review

STIP1  -  stress-induced phosphoprotein 1

Homo sapiens

Synonyms: HEL-S-94n, HOP, Hop, Hsc70/Hsp90-organizing protein, IEF-SSP-3521, ...
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Disease relevance of STIP1

  • Expression of the cDNA in AMA cells using the vaccinia virus expression system followed by two-dimensional gel electrophoresis showed that the protein comigrated with IEF SSP 3521 [1].
  • The sequences show a striking similarity to the sequence of a 63-kDa human protein (IEF SSP 3521) whose abundance is increased in MRC-5 fibroblasts following simian virus 40 transformation [2].
  • We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)--human cerebellar tumors--onto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60) [3].
  • This report describes the cytoskeleton nature of a 60,000-mol-wt protein, P60, previously shown to undergo Ca2+ influx-induced phosphorylation concomitant with insulin release in hamster insulinoma cells [4].
  • Infarction conforming to the interpeduncular profundus arterial territory caused a supranuclear vertical gaze paresis, severe neuropsychological deficits and a delay in the P60 component of the SER [5].
  • We report that STI1 is secreted by and induces proliferation in tumor cells, an effect that is modulated by the Erk and PI3K pathways, and that, in contrast to glioma cells, STI1 does not induce proliferation of normal glia [6].

Psychiatry related information on STIP1

  • Herein, we used an aversively motivated learning paradigm in rats to investigate whether STI1 interaction with PrP(C) affects short-term memory (STM) formation and long-term memory (LTM) consolidation [7].
  • The most frequent diagnoses of the patients with normal PTSEPs (conversion disorder and definite or suspected multiple sclerosis) were significantly less prevalent in the patients with the Absent P60 pattern, while miscellaneous other diseases affecting the peripheral and/or central sensory pathways were more frequent [8].

High impact information on STIP1

  • The TPR1 domain of Hop specifically recognizes the C-terminal heptapeptide of Hsp70 while the TPR2A domain binds the C-terminal pentapeptide of Hsp90 [9].
  • Several phage-encoded peptidoglycan hydrolases have been found to share a conserved amidase domain with a variety of bacterial autolysins (N-acetylmuramoyl-L-alanine amidases), bacterial and eukaryotic glutathionylspermidine amidases, gamma-D-glutamyl-L-diamino acid endopeptidase and NLP/P60 family proteins [10].
  • The Tic40 C-terminal domain, which is homologous to the C terminus of cochaperones Sti1p/Hop and Hip but with no known function, stimulates adenosine triphosphate hydrolysis by Hsp93 [11].
  • Moreover, PrP(c) interaction with either STI1 or with the peptide we found that represents the binding domain in STI1 induce neuroprotective signals that rescue cells from apoptosis [12].
  • Four lines of evidence suggest that P60 is an intermediate filament protein of the keratin class [4].

Chemical compound and disease context of STIP1

  • METHODS: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium-pilocarpine model of secondarily generalized seizure in the rat by using naïve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60) [13].
  • Morphine-induced hyperthermia was first detected at P60 and peaked by P90-P120 [14].

Biological context of STIP1

  • In contrast with the yeast system, human Hop has little effect on the basal rate of ATP hydrolysis but significantly inhibits the client-protein stimulated rate [15].
  • These data suggest steric hindrance between Hap46 and Hop/p60 during interaction with distantly located binding sites on hsp70s [16].
  • We conclude that Hop per se does not set the threshold for susceptibility to GzmB-induced apoptosis [17].
  • Expression of the two cleavage fragments of Hop did not induce cell death [17].
  • We have applied this method to the heat shock protein (Hsp) protein-folding system, studying the network between Hsp70, Hsp90, and Hop (heat shock-organizing protein) [18].

Anatomical context of STIP1

  • A transformation-sensitive human protein (IEF SSP 3521) that is 2-fold up-regulated in SV40-transformed MRC-5 fibroblasts has been purified by two-dimensional gel electrophoresis, microsequenced, and cDNA cloned using oligodeoxyribonucleotides [1].
  • We show that Hop is involved in the process of refolding thermally denatured firefly luciferase in rabbit reticulocyte lysate [19].
  • The antibody also permitted the identification of P60 in normal pancreatic islets as determined both by immunoblotting of hamster islet proteins resolved by two-dimensional electrophoresis and by indirect immunofluorescence microscopy on cryostat sections of hamster pancreas [4].
  • Using P60H as reference, the P60 cells cultured in a methionine medium had slightly lower TCII receptor activity and normal total cobalamin content, a moderately reduced microsomal and mitochondrial cobalamin(III) reductase activity but only trace amounts of the methylcobalamin and adenosylcobalamin cofactors [20].
  • Additionally, the completed genome sequence revealed genes encoding proteins potentially anchored in the cell membrane by a hydrophobic tail as well as genes encoding P60-like proteins and lipoproteins [21].

Associations of STIP1 with chemical compounds

  • Similar to Hop, CyP40 was shown not to influence the adenosine triphosphatase activity of Hsc70 [22].
  • Unlike human fibroblasts, in which the recovery of 6-thioguanine-resistant mutants is reduced by contact feeding when the inoculum size during selection is increased above 10(4) cells per P60 dish, 5 to 10 X 10(4) RuBa 7E cells can be plated per P60 dish without reducing mutant recovery [23].
  • This regulatory network is most prominent in the methionine-dependent P60 cells harboring a disruption of the network in the proximity of cobalamin(III) reductase [20].
  • The Ca2+-dependent increase in phosphorylation of P60 was prevented by trifluoperazine [24].
  • The enhanced 32P-labeling of P60 observed in the presence of 50 mM K+ was Ca2+-dependent since omission of extracellular Ca2+ or addition of the Ca2+ channel blocker alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-gamma-aminopropyl]3,4,5-trimethoxyphenylacetonitrile hydrochloride prevented the effect [24].

Physical interactions of STIP1

  • The interaction of TPR2A with the C-terminal pentapeptide of Hsp90 (MEEVD) is identified as the core contact for Hop binding to Hsp90 [25].
  • Thus, Hop/p60 and substrate proteins can form ternary complexes with hsc70 [16].

Other interactions of STIP1

  • These results raise questions about current models for Hop/Hsp70 interaction [26].
  • Taken together, our results suggest that the assembly of hsp70-Hop-hsp90 complexes is selective and influences the conformational state of each protein [27].
  • As judged from respective deletions, the amino-terminal portions of Hap46 and Hop/p60 are involved in this interference [16].
  • The current dogma proposes that Hop functions primarily as an adaptor that directs Hsp90 to Hsp70-client protein complexes in the cytoplasm [28].
  • The co-chaperone Hop, although not essential for the activation of Chk1 in vitro, enhanced the chaperoning process, whereas the co-chaperone p23 did not stimulate the chaperoning reaction [29].

Analytical, diagnostic and therapeutic context of STIP1

  • RT-PCR and Western blotting of whole P6 and P60 retinal preparations was carried out to determine changes in other caspases and key survival mediators at the mRNA and protein level, respectively [30].
  • Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1 [1].
  • Cell surface binding and pull-down experiments showed that recombinant PrP(c) binds to cellular STI1, and co-immunoprecipitation assays strongly suggest that both proteins are associated in vivo [12].
  • We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models [31].
  • An antibody specific for P60, as judged by immunoblotting, was developed in a rabbit [4].


  1. Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1. Honoré, B., Leffers, H., Madsen, P., Rasmussen, H.H., Vandekerckhove, J., Celis, J.E. J. Biol. Chem. (1992) [Pubmed]
  2. Identification of a 60-kilodalton stress-related protein, p60, which interacts with hsp90 and hsp70. Smith, D.F., Sullivan, W.P., Marion, T.N., Zaitsu, K., Madden, B., McCormick, D.J., Toft, D.O. Mol. Cell. Biol. (1993) [Pubmed]
  3. Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers. Kho, A.T., Zhao, Q., Cai, Z., Butte, A.J., Kim, J.Y., Pomeroy, S.L., Rowitch, D.H., Kohane, I.S. Genes Dev. (2004) [Pubmed]
  4. Identification of a calcium-regulated insulinoma cell phosphoprotein as an islet cell keratin. Schubart, U.K., Fields, K.L. J. Cell Biol. (1984) [Pubmed]
  5. Nonhaemorrhagic thalamic infarction. Clinical, neuropsychological and electrophysiological findings in four anatomical groups defined by computerized tomography. Graff-Radford, N.R., Damasio, H., Yamada, T., Eslinger, P.J., Damasio, A.R. Brain (1985) [Pubmed]
  6. STI1 promotes glioma proliferation through MAPK and PI3K pathways. Erlich, R.B., Kahn, S.A., Lima, F.R., Muras, A.G., Martins, R.A., Linden, R., Chiarini, L.B., Martins, V.R., Moura Neto, V. Glia (2007) [Pubmed]
  7. Short-term memory formation and long-term memory consolidation are enhanced by cellular prion association to stress-inducible protein 1. Coitinho, A.S., Lopes, M.H., Hajj, G.N., Rossato, J.I., Freitas, A.R., Castro, C.C., Cammarota, M., Brentani, R.R., Izquierdo, I., Martins, V.R. Neurobiol. Dis. (2007) [Pubmed]
  8. Neurological associations of absent P60 component of the posterior tibial nerve somatosensory evoked potential. Jones, S. J. Neurol. (2003) [Pubmed]
  9. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Scheufler, C., Brinker, A., Bourenkov, G., Pegoraro, S., Moroder, L., Bartunik, H., Hartl, F.U., Moarefi, I. Cell (2000) [Pubmed]
  10. Amidase domains from bacterial and phage autolysins define a family of gamma-D,L-glutamate-specific amidohydrolases. Rigden, D.J., Jedrzejas, M.J., Galperin, M.Y. Trends Biochem. Sci. (2003) [Pubmed]
  11. Stimulation of transit-peptide release and ATP hydrolysis by a cochaperone during protein import into chloroplasts. Chou, M.L., Chu, C.C., Chen, L.J., Akita, M., Li, H.M. J. Cell Biol. (2006) [Pubmed]
  12. Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. Zanata, S.M., Lopes, M.H., Mercadante, A.F., Hajj, G.N., Chiarini, L.B., Nomizo, R., Freitas, A.R., Cabral, A.L., Lee, K.S., Juliano, M.A., de Oliveira, E., Jachieri, S.G., Burlingame, A., Huang, L., Linden, R., Brentani, R.R., Martins, V.R. EMBO J. (2002) [Pubmed]
  13. Diazepam terminates brief but not prolonged seizures in young, naïve rats. Goodkin, H.P., Liu, X., Holmes, G.L. Epilepsia (2003) [Pubmed]
  14. Ontogenesis of morphine-induced behavior in the cat. Burgess, J.W., Villablanca, J.R. Brain Res. (2007) [Pubmed]
  15. Stimulation of the weak ATPase activity of human hsp90 by a client protein. McLaughlin, S.H., Smith, H.W., Jackson, S.E. J. Mol. Biol. (2002) [Pubmed]
  16. Interference between proteins Hap46 and Hop/p60, which bind to different domains of the molecular chaperone hsp70/hsc70. Gebauer, M., Zeiner, M., Gehring, U. Mol. Cell. Biol. (1998) [Pubmed]
  17. Hop Cleavage and Function in Granzyme B-induced Apoptosis. Bredemeyer, A.J., Carrigan, P.E., Fehniger, T.A., Smith, D.F., Ley, T.J. J. Biol. Chem. (2006) [Pubmed]
  18. Functional Coevolutionary Networks of the Hsp70-Hop-Hsp90 System Revealed through Computational Analyses. Travers, S.A., Fares, M.A. Mol. Biol. Evol. (2007) [Pubmed]
  19. Hop modulates Hsp70/Hsp90 interactions in protein folding. Johnson, B.D., Schumacher, R.J., Ross, E.D., Toft, D.O. J. Biol. Chem. (1998) [Pubmed]
  20. Disruption of a regulatory system involving cobalamin distribution and function in a methionine-dependent human glioma cell line. Fiskerstrand, T., Riedel, B., Ueland, P.M., Seetharam, B., Pezacka, E.H., Gulati, S., Bose, S., Banerjee, R., Berge, R.K., Refsum, H. J. Biol. Chem. (1998) [Pubmed]
  21. Surface proteins and the pathogenic potential of Listeria monocytogenes. Cabanes, D., Dehoux, P., Dussurget, O., Frangeul, L., Cossart, P. Trends Microbiol. (2002) [Pubmed]
  22. Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70. Carrello, A., Allan, R.K., Morgan, S.L., Owen, B.A., Mok, D., Ward, B.K., Minchin, R.F., Toft, D.O., Ratajczak, T. Cell Stress Chaperones (2004) [Pubmed]
  23. In vitro chemical mutagenesis and viral transformation of a human endothelial cell strain. Reznikoff, C.A., DeMars, R. Cancer Res. (1981) [Pubmed]
  24. Ca2+-dependent protein phosphorylation and insulin release in intact hamster insulinoma cells. Inhibition by trifluoperazine. Schubart, U.K., Fleischer, N., Erlichman, J. J. Biol. Chem. (1980) [Pubmed]
  25. Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70 x Hop x Hsp90 complexes. Brinker, A., Scheufler, C., Von Der Mulbe, F., Fleckenstein, B., Herrmann, C., Jung, G., Moarefi, I., Hartl, F.U. J. Biol. Chem. (2002) [Pubmed]
  26. Multiple domains of the co-chaperone Hop are important for Hsp70 binding. Carrigan, P.E., Nelson, G.M., Roberts, P.J., Stoffer, J., Riggs, D.L., Smith, D.F. J. Biol. Chem. (2004) [Pubmed]
  27. The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex. Hernández, M.P., Sullivan, W.P., Toft, D.O. J. Biol. Chem. (2002) [Pubmed]
  28. Hop: more than an Hsp70/Hsp90 adaptor protein. Odunuga, O.O., Longshaw, V.M., Blatch, G.L. Bioessays (2004) [Pubmed]
  29. Chaperoning checkpoint kinase 1 (Chk1), an Hsp90 client, with purified chaperones. Arlander, S.J., Felts, S.J., Wagner, J.M., Stensgard, B., Toft, D.O., Karnitz, L.M. J. Biol. Chem. (2006) [Pubmed]
  30. Analysis of apoptotic and survival mediators in the early post-natal and mature retina. O'driscoll, C., Donovan, M., Cotter, T.G. Exp. Eye Res. (2006) [Pubmed]
  31. Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Deng, G.M., Zheng, L., Chan, F.K., Lenardo, M. Nat. Med. (2005) [Pubmed]
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