Cited by 416Heat shock proteins researchProtein Kinase Regulation and GTPase SignalingCancer-related Molecular Pathways

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Heat-shock protein hsp90 governs the activity of pp60v-src kinase.

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Xu, Y, Lindquist, S·1993·Proceedings of the National Academy of Sciences

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Abstract

During or immediately after synthesis in vertebrate cells, the oncogenic protein-tyrosine kinase pp60v-src associates with the approximately 90-kDa heat-shock protein (hsp90). In this complex, pp60v-src is not functional as a kinase. When pp60v-src is subsequently found inserted into the plasma membrane, it is active as a kinase and is no longer associated with hsp90. We have taken advantage of genetic manipulations possible in Saccharomyces cerevisiae to investigate the function and specificity of the association between hsp90 and pp60v-src. Expression of pp60v-src is known to be toxic to S. cerevisiae cells. We find that this toxicity is due to a very specific effect on growth, arrest at a particular point in the cell cycle. In cells expressing v-src, a mutation that lowers the level of hsp90 expression (i) relieves cell cycle arrest and rescues growth, (ii) reduces the level of tyrosine phosphorylation mediated by pp60v-src, (iii) changes the pattern of tyrosine phosphorylation, and (iv) reduces the concentration of pp60v-src. We conclude that hsp90 does not simply suppress pp60v-src kinase activity during transit to the plasma membrane, as previously suggested, but also stabilizes the protein and affects both its activity and specificity. This function of hsp90 is highly selective for pp60v-src: the same hsp90 mutation has no effect on the activity or specificity of the exogenous pp160v-abl tyrosine kinase; similarly, it does not affect the specificity and has only a very small effect on the activity of the exogenous pp60c-src kinase.

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Background
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“…hormone receptors (Pratt and Toft 1997), mutated p53 (Blagosklonny et al. 1995), and several oncogenic tyrosine and serine/threonine kinases, including v-src (Xu and Lindquist 1993), Raf-1 (Stancato et al. 1993) and ErbB-2 (Xu et al. 2001), can be recovered as heterocomplexes containing Hsp90.”
Background
CDC37 is required for p60v-src activity in yeast.
Dey, B., Lightbody, J. J., & Boschelli, F. (1996) · Molecular Biology of the Cell · doi:10.1091/mbc.7.9.1405 · Cited by 73
The Mechanism of Hsp90 ATPase Stimulation by Aha1
Wolmarans, A., Lee, B., Spyracopoulos, L., & LaPointe, P. (2016) · Scientific Reports · doi:10.1038/srep33179 · Cited by 72
Chaperoning stem cells: a role for heat shock proteins in the modulation of stem cell self‐renewal and differentiation?
Prinsloo, E., Setati, M. M., Longshaw, V. M., & Blatch, G. L. (2009) · BioEssays · doi:10.1002/bies.200800158 · Cited by 69
“,SRCfamilykinases(SRC, LCK),((31,32)) serine/threonine kinases (RAF-1, AKT),((33,34)) cell cycle G2 checkpoint kinases (POLO-1), (35) mutant fusion kinases (NPM-ALK),((36)) steroid hormone receptors (glucocorticoid, progesterone), transcription factors (p53, HSF1),((40,41)) and human telomerase reverse transcriptase (…”
Background
Gα12 regulates protein interactions within the MDCK cell tight junction and inhibits tight-junction assembly
Sabath, E., Negoro, H., Beaudry, S., Paniagua, M., Angelow, S., Shah, J. V., Grammatikakis, N., Yu, A. S. L., & Denker, B. M. (2008) · Journal of Cell Science · doi:10.1242/jcs.014878 · Cited by 72
“Hsp90 interacts with both G 12 (Vaiskunaite et al., 2001; Waheed and Jones, 2002) and Src (Xu and Lindquist, 1993), so we speculated that the Hsp90 chaperone might provide the link between activated G 12 and Src activation.”
Background
The Cdc37 protein kinase–binding domain is sufficient for protein kinase activity and cell viability
Lee, P. C., Rao, J., Fliss, A., Yang, E., Garrett, S., & Caplan, A. J. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200210121 · Cited by 69
The Effects of Chaperones and the Influence of Protein Assembly on Peroxisomal Protein Import
Crookes‐Goodson, W. J., & Olsen, L. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.27.17236 · Cited by 69
Heat shock protein gene expression during embryonic development of the zebrafish
Krone, P. H., Sass, J. B., & Lele, Z. (1997) · Cellular and Molecular Life Sciences · doi:10.1007/pl00000574 · Cited by 68
Advances in the structures, mechanisms and targeting of molecular chaperones
Gu, J., He, Y., He, C., Zhang, Q., Huang, Q., Bai, S., Wang, R., You, Q., & Wang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02166-2 · Cited by 79
“It 301 – 303 As HSPs play complex and precise roles in regulating numerous client proteins, they are related to various types of diseases.”
HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance
Song, D., Guo, M. Z., Xu, S., Xiaotian, S., Bai, B., Li, Z., Chen, J., An, Y., Nie, Y., Wu, K., et al. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01951-5 · Cited by 65
Mutational analysis of Hsp90α dimerization and subcellular localization: dimer disruption does not impede ‘in vivo’ interaction with estrogen receptor
Meng, X., Devin, J., Sullivan, W. P., Toft, D. O., Baulieu, É.-É., & CATELLI, M. G. (1996) · Journal of Cell Science · doi:10.1242/jcs.109.7.1677 · Cited by 65
Hsp90 chaperone complexes are required for the activity and stability of yeast protein kinases Mik1, Wee1 and Swe1
Goes, F. S., & Martin, J. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02105.x · Cited by 64
The Ydj1 molecular chaperone facilitates formation of active p60v-src in yeast.
Dey, B., Caplan, A. J., & Boschelli, F. (1996) · Molecular Biology of the Cell · doi:10.1091/mbc.7.1.91 · Cited by 63
The Sch9 protein kinase regulates Hsp90 chaperone complex signal transduction activity in vivo
Morano, K. A., & Thiele, D. J. (1999) · The EMBO Journal · doi:10.1093/emboj/18.21.5953 · Cited by 62
“For example, the activity and levels of two cell cycle regulatory kinases, mammalian v-src expressed in yeast (Xu and Lindquist, 1993) and endogenous Wee1 in the yeast Schizosaccharomyces pombe (Aligue et al.”
Background
Inhibition of heat shock protein 90 sensitizes melanoma cells to thermosensitive ferromagnetic particle‐mediated hyperthermia with low Curie temperature
Ito, A., Saito, H., Mitobe, K., Minamiya, Y., Takahashi, N., Maruyama, K., Motoyama, S., Katayose, Y., & Ogawa, J. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2008.01072.x · Cited by 61
Keep your heart in shape: molecular chaperone networks for treating heart disease
Tarone, G., & Brancaccio, M. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu049 · Cited by 61
“Most Hsp90 clients are signal transduction proteins,(74,75) such as Src, Raf, Akt, PI3K, Pdk1, and eNos.(76) –78 Hsp90 interaction with kinases involves the co-chaperone protein Cdc37.”
Regulation of pulmonary endothelial barrier function by kinases
Barabutis, N., Verin, A. D., & Catravas, J. D. (2016) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00233.2016 · Cited by 61
Transmembrane signaling in Saccharomyces cerevisiae as a model for signaling in metazoans: State of the art after 25years
Engelberg, D., Perlman, R., & Levitzki, A. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.09.003 · Cited by 61
The Yeast CDC37 Gene Interacts with MPS1 and Is Required for Proper Execution of Spindle Pole Body Duplication
Schutz, A. R., Giddings, T. H., Steiner, E., & Winey, M. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.136.5.969 · Cited by 60
“Activity of this kinase requires two yeast chaperone genes: HSP90 (Xu and Lindquist, 1993; Nathan and Lindquist, 1995) and YDJ1, a DnaJ homologue (Bohen et”
BackgroundInfluential
Heat Shock Proteins 70 and 90 Increase Calcineurin Activity in Vitro through Calmodulin-Dependent and Independent Mechanisms
Someren, J. S., Faber, L. E., Klein, J. D., & Tumlin, J. A. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0800 · Cited by 59
G Protein-coupled Receptor Kinase Interaction with Hsp90 Mediates Kinase Maturation
Luo, J., & Benovic, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307637200 · Cited by 58
Interaction of HSP90 to N‐WASP leads to activation and protection from proteasome‐dependent degradation
Park, S. J., Suetsugu, S., & Takenawa, T. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600586 · Cited by 58
“HSP90 is reported to regulate the catalytic activity of v-Src (Xu and Lindquist, 1993; An et al, 2000).”
Background
2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Activation of a Protein Tyrosine Kinase, pp60src, in Murine Hepatic Cytosol Using a Cell-Free System
Blankenship, A. L., & Matsumura, F. (1997) · Molecular Pharmacology · doi:10.1124/mol.52.4.667 · Cited by 58
Heat shock response to vaccinia virus infection
Sedger, L. M., & Ruby, J. C. (1994) · Journal of Virology · doi:10.1128/jvi.68.7.4685-4689.1994 · Cited by 58
Regulation of heat shock gene expression in response to stress
Garbuz, D. G. (2017) · Molecular Biology · doi:10.1134/s0026893317020108 · Cited by 57
Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia
Trentin, L., Frasson, M., Donella‐Deana, A., Frezzato, F., Pagano, M. A., Tibaldi, E. V., Gattazzo, C., Zambello, R., Semenzato, G., & Brunati, A. M. (2008) · Blood · doi:10.1182/blood-2008-02-139139 · Cited by 57
Heat shock protein 90: translation from cancer to Alzheimer's disease treatment?
Luo, W., Rodina, A., & Chiosis, G. (2008) · BMC Neuroscience · doi:10.1186/1471-2202-9-s2-s7 · Cited by 56
“Historically, v-Src kinase was the first oncoprotein shown to display unusually stable interactions with Hsp90 and associated chaperones [8].”
Background
Molecular chaperones and protein folding in plants
Boston, R. S., Viitanen, P. V., & Vierling, E. (1996) · Springer eBooks · doi:10.1007/978-94-009-0353-1_9 · Cited by 56
Molecular chaperoning of steroid hormone receptors
Pratt, W. B., Gehring, U., & Toft, D. O. (1996) · Birkhäuser Basel eBooks · doi:10.1007/978-3-0348-9088-5_6 · Cited by 56
Blind cavefish and heat shock protein chaperones: a novel role for hsp90alpha in lens apoptosis
Hooven, T. A., Yamamoto, Y., & Jeffery, W. R. (2004) · The International Journal of Developmental Biology · doi:10.1387/ijdb.041874th · Cited by 54
Identification of Cdc37 as a Novel Regulator of the Stress-Responsive Mitogen-Activated Protein Kinase
Tatebe, H., & Shiozaki, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5132-5142.2003 · Cited by 55
Molecular basis for the actions of Hsp90 inhibitors and cancer therapy
Yamaki, H., Nakajima, M., Shimotohno, K., & Tanaka, N. (2011) · The Journal of Antibiotics · doi:10.1038/ja.2011.60 · Cited by 55
Heat Shock Protein 90: A Unique Chemotherapeutic Target
Cullinan, S. B., & Whitesell, L. J. (2006) · Seminars in Oncology · doi:10.1053/j.seminoncol.2006.04.001 · Cited by 55
A Mouse Homologue of the Drosophila Tumor Suppressor l(2)tid Gene Defines a Novel Ras GTPase-activating Protein (RasGAP)-binding Protein
Trentin, G. A., Yin, X., Tahir, S., Lhoták, Š., Farhang-Fallah, J., Li, Y., & Rozakis-Adcock, M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009267200 · Cited by 54
The molecular chaperone Cdc37 is required for Ste11 function and pheromone‐induced cell cycle arrest
Abbas‐Terki, T., Donzé, O., & Picard, D. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01134-0 · Cited by 53
A comparison of Hsp90α and Hsp90β interactions with cochaperones and substrates
Taherian, A., Krone, P. H., & Ovsenek, N. (2008) · Biochemistry and Cell Biology · doi:10.1139/o07-154 · Cited by 52
“1997), Src (Brugge 1986; Stancato et al. 1997; Xu and Lindquist 1993) Cdk4 (Stepanova et al.”
Background
Genetic interactions between Hsp90 and the Cdc2 mitotic machineryin the fission yeast Schizosaccharomyces pombe
Muñoz, M. J., & Jiménez, J. (1999) · Molecular and General Genetics MGG · doi:10.1007/s004380050963 · Cited by 52
“The Hsp90 heat shock protein in a complex with other co-chaperone partners forms strong associations with steroid hormone receptors (Johnson and Toft 1994; Dittmar et al. 1996), basic helix-loop-helix transcription factors (Shue and Kohtz 1994), oncogenic tyrosine kinases ( Xu and Lindquist 1993 ) and serine-threonine…”
Background

Authors: Xu, Y., & Lindquist, S.
Affiliations: University of Chicago (US)
Howard Hughes Medical Institute (US)
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1993-08
Volume: 90
Issue: 15
Pages: 7074-7078
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.90.15.7074
PMC: PMC47078
OpenAlex: W2085643470
Cited by: 416
References: 33
Citations by year: 2026: 2 · 2025: 4 · 2024: 10 · 2023: 7 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 11 · 2018: 11 · 2017: 13 · 2016: 10 · 2015: 5 · 2014: 14 · 2013: 5 · 2012: 12
FWCI: 5.67
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: University of Chicago
National Institutes of Health
National Institute of General Medical Sciences (GM-25874)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: HSP90, pp60v-src, tyrosine kinase, kinase activation, protein stability, cell cycle arrest, tyrosine phosphorylation, oncogenic kinase, Src kinase, Saccharomyces cerevisiae, kinase specificity
MeSH terms: Cell Cycle, Chromosome Deletion, Genes, Fungal, Heat-Shock Proteins, Phosphoproteins, Recombinant Proteins, Saccharomyces cerevisiae, Tyrosine, Oncogene Protein pp60(v-src), Gene Expression, Mutagenesis, Insertional, Oncogene Proteins v-abl, Proto-Oncogene Proteins pp60(c-src), Phosphotyrosine

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Heat-shock protein hsp90 governs the activity of pp60v-src kinase.

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