Proteomics

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In vitro reconstitution of Sgk3 activation by phosphatidylinositol-3-phosphate

ABSTRACT: Serum- and glucocorticoid-regulated kinase 3 (Sgk3) is activated by the phospholipid 19 phosphatidylinositol-3-phosphate (PI3P) downstream of growth factor signaling and 20 by Vps34-mediated PI3P production during autophagy. Upregulation of Sgk3 activity 21 has been linked to a number of human cancers due to its overlapping substrate 22 specificity with Akt. Here, we show that Sgk3 is regulated by a combination of 23 phosphorylation and allosteric activation by PI3P. We demonstrate that Sgk3 is 24 specifically activated by PI3P and that PI3P binding induces large conformational 25 changes in Sgk3. Using Vps34 and liposomes containing phosphatidylinositol, we 26 reconstitute Sgk3 signaling via Vps34-mediated PI3P synthesis in vitro. In addition to 27 defining the mechanism of Sgk3 activation by PI3P, our findings open up potential 28 therapeutic avenues in allosteric inhibitor development to target Sgk3 in cancer.

INSTRUMENT(S): impact HD

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John Burke  

LAB HEAD: Dr. John E Burke

PROVIDER: PXD025327 | Pride | 2021-09-22

REPOSITORIES: Pride

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In vitro reconstitution of Sgk3 activation by phosphatidylinositol 3-phosphate.

Pokorny Daniel D   Truebestein Linda L   Fleming Kaelin D KD   Burke John E JE   Leonard Thomas A TA  

The Journal of biological chemistry 20210625 2

Serum- and glucocorticoid-regulated kinase 3 (Sgk3) is a serine/threonine protein kinase activated by the phospholipid phosphatidylinositol 3-phosphate (PI3P) downstream of growth factor signaling via class I phosphatidylinositol 3-kinase (PI3K) signaling and by class III PI3K/Vps34-mediated PI3P production on endosomes. Upregulation of Sgk3 activity has recently been linked to a number of human cancers; however, the precise mechanism of activation of Sgk3 is unknown. Here, we use a wide range o  ...[more]

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