Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt

Mol Cell. 2016 Jun 16;62(6):929-942. doi: 10.1016/j.molcel.2016.04.023. Epub 2016 May 26.

Abstract

The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper-phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D or using CDK4/6 inhibitors releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Proliferation / drug effects
  • Cyclin D / genetics
  • Cyclin D / metabolism
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Enzyme Activation
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Molecular Targeted Therapy
  • Multiprotein Complexes / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Retinoblastoma Protein / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Cyclin D
  • MAPKAP1 protein, human
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6