The Platelet-derived Growth Factor Receptor Is Destabilized by Geldanamycins in Cancer Cells

Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2007; 282(1):445-53. DOI: 10.1074/jbc.M607012200
Source: PubMed


The heat shock protein HSP90 serves as a chaperone for receptor protein kinases, steroid receptors, and other intracellular signaling molecules. Targeting HSP90 with ansamycin antibiotics disrupts the normal processing of clients of the HSP90 complex. The platelet-derived growth factor receptor alpha (PDGFRalpha) is a tyrosine kinase receptor up-regulated and activated in several malignancies. Here we show that the PDGFRalpha forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma, and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRalpha with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes degradation of the receptor. Likewise, phospho-Akt, a downstream target, is degraded after treatment with 17-AAG. In contrast, PDGFRalpha expression is not affected by 17-AAG in normal human smooth muscle cells or 3T3 fibroblasts. PDGFRalpha degradation by 17-AAG is inhibited by the proteasome inhibitor MG132. High molecular weight, ubiquitinated forms of the receptor are detected in cells treated with 17-AAG and MG132. Degradation of the receptor is also inhibited by a specific neutralizing antibody to the PDGFRalpha but not by a neutralizing antibody to PDGF or by imatinib mesylate (Gleevec). Ultimately, PDGFRalpha-mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRalpha degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases but also overexpressed receptors in cancer cells can be targeted by 17-AAG.

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    • "[271] CCRP Retains CAR and PXR in the cytoplasm associated to microtubules [258] UNC-45 Favors assembly of myosin and myogenesis [272] Tom70 Facilitates mitochondrial import of proteins [273] CHIP Remodels Hsp90-client proteins targeting them to proteosomal degradation [274] SGT1 Required for kinetochore complex assembly and innate immunity in plants and animals [275] [276] Kinases pp60-vSrc Required for Src-mediated cell transformation [277] Raf1 Essential for Raf-kinase activity and ternary assembly with Cdc37 [278] eEF2-K Prevents aggregation and activates kinase activity [279] p210 Bcr-Abl Stabilizes de complex preventing its proteosomal degradation [280] Akt Essential for kinase activity and stability of complexes with Cdc37 [281] Chk1 Favors kinase activity [282] ErB2 Stabilizes and restrains ErbB2 from interacting with other ErbBs in the absence of ligand [283] [284] PDK Stabilizes PDK without affecting the intrinsic enzymatic activity of kinase [285] IκB kinase (IKK) Favors assembly, translocation, and activation of IKKs [286] IGF1R Permits the transduction of the signaling cascade of the receptor [287] Insulin R Receptor trafficking to cytosol. Mobility in the endoplasmic reticulum during maturation [288] [289] VEGFR Favors the development of focal contacts at the receptor site via FAK activation [290] PDGFR Required for receptor maturation and oligomerization with cdc37 [291] [292] TrkA Favors the localization of the receptor in the cell surface [293] Cdk1 Forms complexes with cdc37 [294] JAK Forms complexes with cdc37 [295] p38 Forms complexes with cdc37 attenuating p38 autophosphorylation [296] PKC Required for phosphorylation, stability, mitochondrial and nuclear import [94] [297] [298] DNA-PK Proapoptotic response [217] PARK Possible enhancer of Akt-dependent actions [299] CMDKs Required for fungus transformation [300] Cdk4 Stabilizes complexes with cdc37 [301] MEKK (o MAP3k) Stabilizes complexes and favors kinase activity [302] EPHA7-R Required for kinase activity [303] GSK3 Required for autophosphorylation and stability [235] [304] Structural proteins Histones Induces chromatin condensation [305] Actin Modulates microfilaments assembly [306] Myosin Favors myofilaments assembly and myogenesis [307] Tubulin Protects against thermal denaturation and preserves microtubule polymerization [308] Lamin A/C Possible post-translational modifications [309] Vimentin Prevents cleavage by caspases [310] Keratins Enables protein unfolding and translocation to lysosomes [311] Neurofilaments Prevents protein aggregation and axonal degeneration [312] Nup62 Favors interaction of the GR with the nuclear pore complex and its nuclear translocation [171] Others p23 Client protein stabilization/maturation. Prostaglandin E2 synthase activity is enhanced [313] [314] Hsp70 Regulates client protein function, trafficking and turnover. "
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    • "More recently it has been shown that Cdc37 is essential for maintaining prostate tumor cell growth [23]. Additionally, the platelet-derived growth factor receptor alpha which is up-regulated and activated in several malignancies forms a complex with HSP90 and the co-chaperone Cdc37 in ovarian, glioblastoma, and lung cancer cells [24]. Together, these results support the targeting of Cdc37 for cancer therapy. "
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