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Comment
. 2008 Feb 5;105(5):1389-90.
doi: 10.1073/pnas.0711993105. Epub 2008 Jan 29.

IP6K2 is a client for HSP90 and a target for cancer therapeutics development

David S Shames  1 , John D Minna
Affiliations
Comment

IP6K2 is a client for HSP90 and a target for cancer therapeutics development

David S Shames et al. Proc Natl Acad Sci U S A. .
No abstract available

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Schematic representation of HSP90 binding to client proteins, how these proteins affect six hallmarks of cancer, and drug target sites within HSP90. HSP90 interacts with proteins that contribute to all six hallmarks of cancer (for a complete list of HSP90 binding partners see ref. 16). HSP90 binds to many of the expressed kinase domains within the human genome. HSP90 stabilizes the active conformations of both WT and mutant tyrosine kinase receptors (red-purple), cytosolic serine-threonine and tyrosine kinases (green), transcription factors (blue), structural proteins and other enzymes (gray). Note: no specific sequence within the middle domain as a binding site is implied by the cartoon. Client binding occurs through the middle domain of HSP90 (purple rectangle), which leads to HSP90 dimerization, cochaperone binding (HSP70, HIP, HOP, cdc37), and ATP binding and hydrolysis. Many of these interactions are inhibited by small molecules that compete for the N-terminal ATP binding pocket such as the benzoquinone ansamycins (geldanamycin, 17-AAG), radicicols, their derivatives, and purine analogues (PU) (see refs. and 8). Thus, many signal transduction pathways require HSP90 to perpetuate growth promoting signals, and attenuation of these signals by inhibition of HSP90 ATPase activity leads indirectly to cell death. On the other hand, proteins that bind to the C terminus (green rectangle) of HSP90, such as FKBP38 and IP6K2, are maintained in a constitutively inactive state by the interaction (red border). Drugs such as cisplatin and novobiocin (which interact with the C terminus of HSP90 at high concentrations) appear to disrupt these interactions, leading to the release and activation of the now cytosolic c-terminal binding partners (green border) and subsequent apoptosis, either through inhibition of Bcl2 (FKBP38) or increased cytosolic concentrations of IP7 (IP6K2). Dashed arrows indicate interactions that have yet to be demonstrated biochemically.
See this image and copyright information in PMC

Comment on

  • HSP90 regulates cell survival via inositol hexakisphosphate kinase-2.
    Chakraborty A, Koldobskiy MA, Sixt KM, Juluri KR, Mustafa AK, Snowman AM, van Rossum DB, Patterson RL, Snyder SH. Chakraborty A, et al. Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1134-9. doi: 10.1073/pnas.0711168105. Epub 2008 Jan 14. Proc Natl Acad Sci U S A. 2008. PMID: 18195352 Free PMC article.

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