Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4.

Stepanova, Lilia; Leng, Xiaohong; Parker, Susan; Harper, J. Wade

doi:10.1101/gad.10.12.1491

Cited by 459 publications

(494 citation statements)

References 47 publications

Supporting

Mentioning

450

Contrasting

Unclassified

Order By: Relevance

“…Similar to most of the Hsp90 client kinases, Cdks are recruited to Hsp90 by Cdc37 (Caplan et al 2007). Interestingly, early studies devoted to the interactions between Hsp90/Cdc37 and the members of Cdk family identified Cdk4 and Cdk6, whereas other Cdks failed to interact with Hsp90/Cdc37 (Stepanova et al 1996;Lamphere et al 1997). Only recently, Cdk2 has been shown to be a genuine client kinase of Hsp90/Cdc37 (Prince et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Novel Hsp90 partners discovered using complementary proteomic approaches

Tsaytler

Krijgsveld

Goerdayal

et al. 2009

Cell Stress and Chaperones

View full text Add to dashboard Cite

Hsp90 is an essential eukaryotic molecular chaperone that stabilizes a large set of client proteins, many of which are involved in various cellular signaling pathways. The current list of Hsp90 interactors comprises about 200 proteins and this number is growing steadily. In this paper, we report on the application of three complementary proteomic approaches directed towards identification of novel proteins that interact with Hsp90. These methods are coimmunoprecipitation, pull down with biotinylated geldanamycin, and immobilization of Hsp90β on sepharose. In all, this study led to the identification of 42 proteins, including 18 proteins that had not been previously characterized as Hsp90 interactors. These novel Hsp90 partners not only represent abundant protein species, but several proteins were identified at low levels, among which signaling kinase Cdk3 and putative transcription factor tripartite motif-containing protein 29. Identification of tetratricopeptide-repeat-containing mitochondrial import receptor protein Tom34 suggests the involvement of Hsp90 in the early steps of translocation of mitochondrial preproteins. Taken together, our data expand the knowledge of the Hsp90 interactome and provide a further step in our understanding of the Hsp90 chaperone system.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel Hsp90 partners discovered using complementary proteomic approaches

Tsaytler

Krijgsveld

Goerdayal

et al. 2009

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…p50 is a kinase specific co-chaperone and is thought to assist in the transfer of kinases to Hsp90 (Grammatikakis et al, 1999;Lee et al, 2002;Stepanova et al, 1996). Domain mapping has shown that p50's N-terminal domain is critical for binding kinases whereas the middle and C-terminal domains interact with Hsp90 (Grammatikakis et al, 1999;Roe et al, 2004;Shao et al, 2003).…”

Section: P50 a Kinase Specific Co-chaperone Also Traps Hsp90 In An mentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

278

262

View full text Add to dashboard Cite

The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

show abstract

“…Other kinases may be stabilized by additional intramolecular domains and/or by regulatory partner proteins that bring stability along with substrate specificity 23 . For instance Cdk4 binds initially to Hsp90 and Cdc37 until encountering cyclin D1 and forming a Cdk4-Cyclin D1 complex sufficiently stable to be independent of further chaperone interaction 25 . Other kinases such as the oncogenic c-erb-B2 bind persistently to chaperone complexes even in the active form (reviewed 2 ).…”

Section: Structural Mechanisms Of Cdc37-kinase Interactionmentioning

confidence: 99%

Targeting the oncogene and kinome chaperone CDC37

et al. 2008

View full text Add to dashboard Cite

Cdc37 is a molecular chaperone that physically stabilizes the catalytic domains found in protein kinases and is therefore a wide-spectrum regulator of protein phosphorylation. It is also an overexpressed oncogene that mediates carcinogenesis by stabilizing the compromised structures of mutant and/or overexpressed oncogenic kinases. Recent work shows that such dependency of malignant cells on elevated Cdc37 expression is a vulnerability that can be targeted in cancer by agents that deplete or inhibit Cdc37. Cdc37 is thus a candidate for broad-spectrum molecular cancer therapy.Although Cdc37 is overexpressed in a number of cancers, it is an unusual oncoprotein whose transforming character does not readily snap into place in the conventional oncogenic pathways. Instead, it is a molecular chaperone, a protein that facilitates folding/refolding of other proteins, often described as its "clients". The role of molecular chaperones in cancer was first characterized with regard to Hsp90 (for review see 5 ). Hsp90 is a facilitator of oncogenesis that stabilizes a wide range of overexpressed or mutated oncogenic proteins and permits their tumorigenic influence to arise 3,7 . Tumors thus appear to become addicted to chaperones and can be treated by withdrawing the chaperoning power of Hsp90 [4][5][6] . Cdc37 interacts with a subset of client proteins within Hsp90 complexes and plays a specialized role as primary partner in kinome maintenance 3,8,9 . This specialized property of Cdc37 fuels the acceleration of cell proliferation observed in cancer by promoting the activities of a broad array of protein kinases 1-3 . These include receptor tyrosine kinases such as EGFR and MET, non-receptor tyrosine kinases v-src and Lck, and intracellular serine/threonine kinases Raf-1, Ksr, Akt, IKK, Cdc2, Cdk2 and Cdk4. A comprehensive list of Cdc37 client kinases, including the ones listed above and others can be found at the website of Dr Didier Picard: http://www.picard.ch/downloads/Cdc37interactors.pdf. The degree of dependency of the cancer cell kinome on Cdc37 expression thus appears to be extensive and in a recent yeast screen, at least 90 % of the protein kinases examined required Cdc37 for function 10 .The defining cellular role for Cdc37, which becomes misappropriated in cancer, resides in its promotion of cell proliferation. Indeed this protein was first discovered in a yeast screen for cell division cycle proteins, hence its name 11 . Thus when mammalian tissues undergo rapid proliferation during development, the normally scarce levels of Cdc37 are rapidly expanded. Elevated levels of Hsp90/Cdc37 complexes mediate the maturation and stabilization of protein 3Correspondence to: Stuart K. Calderwood, 21-27 Burlington Ave. Rm. 553B, Boston, MA 02215, scalderw@bidmc.harvard.edu. 2 Current address: Johns Hopkins University School of Medicine, Baltimore, MD 21205Because of space limitations we were unable to cite many significant studies on Cdc37 and Hsp90. We apologize to the authors of such studies and refer to excellent pu...

show abstract

Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4.

Cited by 459 publications

References 47 publications

Novel Hsp90 partners discovered using complementary proteomic approaches

Novel Hsp90 partners discovered using complementary proteomic approaches

Conformational dynamics of the molecular chaperone Hsp90

Targeting the oncogene and kinome chaperone CDC37

Contact Info

Product

Resources

About