Mechanism of activation of SGK3 by growth factors-via the Class 1 and Class 3 PI3Ks

Nazma Malik (Lead / Corresponding author), Thomas Macartney, Annika Hornberger, Karen Anderson, Hannah Tovell, Alan R. Prescott, Dario R. Alessi (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
267 Downloads (Pure)

Abstract

Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3 promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its PX domain binding to PtdIns(3)P. Here we demonstrate that endogenous SGK3 is rapidly activated by growth factors such as IGF1, through pathways involving both Class 1 and Class 3 PI3Ks. We provide evidence that IGF1 enhances endosomal PtdIns(3)P levels via a pathway involving the UV-RAG complex of hVPS34 Class 3 PI3K. Our data points towards IGF1 induced activation of Class 1 PI3K stimulating SGK3 through enhanced production of PtdIns(3)P resulting from the dephosphorylation of PtdIns(3,4,5)P3 Our findings are also consistent with activation of Class 1 PI3K promoting mTORC2 phosphorylation of SGK3 and with oncogenic Ras activating SGK3 solely through the Class 1 PI3K pathway. Our results highlight the versatility of upstream pathways that activate SGK3 and help explain how SGK3 substitutes for Akt following inhibition of Class 1 PI3K/Akt pathways. They also illustrate robustness of SGK3 activity that can remain active and counteract physiological conditions or stresses where either Class 1 or Class 3 PI3K pathways are inhibited.

Original languageEnglish
Pages (from-to)117-135
Number of pages19
JournalBiochemical Journal
Volume475
Issue number1
Early online date17 Nov 2017
DOIs
Publication statusPublished - 2 Jan 2018

Keywords

  • hVPS34/VPS34
  • Kinases
  • Phosphoinositide 3-kinase
  • Insulin-like growth factor
  • Akt
  • mTOR
  • PDK1
  • SHIP2
  • UVRag/UV-RAG
  • Class I Phosphatidylinositol 3-Kinases/genetics
  • Phosphatidylinositol Phosphates/metabolism
  • Signal Transduction
  • Humans
  • Gene Expression Regulation
  • Plasmids/chemistry
  • Protein-Serine-Threonine Kinases/genetics
  • Proto-Oncogene Proteins c-akt/genetics
  • Class III Phosphatidylinositol 3-Kinases/genetics
  • Insulin-Like Growth Factor I/metabolism
  • Endosomes/drug effects
  • Transfection
  • HEK293 Cells
  • Mechanistic Target of Rapamycin Complex 2/genetics
  • Phosphorylation/drug effects

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