Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System
Summary: Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blo...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717314894 |
| _version_ | 1831633751261577216 |
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| author | Stephen T. Hallett Martyna W. Pastok R. Marc L. Morgan Anita Wittner Katie L.I.M. Blundell Ildiko Felletar Stephen R. Wedge Chrisostomos Prodromou Martin E.M. Noble Laurence H. Pearl Jane A. Endicott |
| author_facet | Stephen T. Hallett Martyna W. Pastok R. Marc L. Morgan Anita Wittner Katie L.I.M. Blundell Ildiko Felletar Stephen R. Wedge Chrisostomos Prodromou Martin E.M. Noble Laurence H. Pearl Jane A. Endicott |
| author_sort | Stephen T. Hallett |
| collection | DOAJ |
| description | Summary: Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions. : Hallett et al. reconstitute CDK4/6 client kinase handover from Cdc37-Hsp90 to CDK regulatory partners and propose a model for the assembly factor activity of CIP/KIP CDK inhibitors. They find that CDK4/6 inhibitors in clinical use can displace G1 CDKs from the Cdc37-Hsp90 chaperone system at submicromolar concentrations. Keywords: Cdc37, CDK, chaperone, CIP/KIP, cyclin D, Hsp90, INK, kinase, palbociclib, ribociclib |
| first_indexed | 2024-12-19T05:42:17Z |
| format | Article |
| id | doaj.art-47f3367cf8e14eb7a9f180a5866f49b6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-19T05:42:17Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-47f3367cf8e14eb7a9f180a5866f49b62022-12-21T20:33:59ZengElsevierCell Reports2211-12472017-10-0121513861398Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone SystemStephen T. Hallett0Martyna W. Pastok1R. Marc L. Morgan2Anita Wittner3Katie L.I.M. Blundell4Ildiko Felletar5Stephen R. Wedge6Chrisostomos Prodromou7Martin E.M. Noble8Laurence H. Pearl9Jane A. Endicott10Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UKNewcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UKGenome Damage and Stability Centre, School of Life Sciences, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UKNewcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UKGenome Damage and Stability Centre, School of Life Sciences, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UKGenome Damage and Stability Centre, School of Life Sciences, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UKNewcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UKGenome Damage and Stability Centre, School of Life Sciences, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UKNewcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UKGenome Damage and Stability Centre, School of Life Sciences, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UK; Corresponding authorNewcastle Cancer Centre, Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Corresponding authorSummary: Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions. : Hallett et al. reconstitute CDK4/6 client kinase handover from Cdc37-Hsp90 to CDK regulatory partners and propose a model for the assembly factor activity of CIP/KIP CDK inhibitors. They find that CDK4/6 inhibitors in clinical use can displace G1 CDKs from the Cdc37-Hsp90 chaperone system at submicromolar concentrations. Keywords: Cdc37, CDK, chaperone, CIP/KIP, cyclin D, Hsp90, INK, kinase, palbociclib, ribociclibhttp://www.sciencedirect.com/science/article/pii/S2211124717314894 |
| spellingShingle | Stephen T. Hallett Martyna W. Pastok R. Marc L. Morgan Anita Wittner Katie L.I.M. Blundell Ildiko Felletar Stephen R. Wedge Chrisostomos Prodromou Martin E.M. Noble Laurence H. Pearl Jane A. Endicott Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System Cell Reports |
| title | Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System |
| title_full | Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System |
| title_fullStr | Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System |
| title_full_unstemmed | Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System |
| title_short | Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System |
| title_sort | differential regulation of g1 cdk complexes by the hsp90 cdc37 chaperone system |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717314894 |
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