AMPK and AKT protein kinases hierarchically phosphorylate the N-terminus of the FOXO1 transcription factor, modulating interactions with 14-3-3 proteins
Artikel i vetenskaplig tidskrift, 2019

Forkhead box protein O1 (FOXO1) is a transcription factor involved in various cellular processes such as glucose metabolism, development, stress resistance, and tumor suppression. FOXO1's transcriptional activity is controlled by different environmental cues through a myriad of posttranslational modifications. In response to growth factors, the serine/threonine kinase AKT phosphorylates Thr24 and Ser256 in FOXO1 to stimulate binding of 14-3-3 proteins, causingFOXO1inactivation. In contrast, low nutrient and energy levels induce FOXO1 activity. AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, partly mediates this effect through phosphorylation of Ser383 and Thr649 in FOXO1. In this study, we identified Ser22 as an additional AMPK phosphorylation site in FOXO1's N terminus, with Ser22 phosphorylation preventing binding of 14-3-3 proteins. The crystal structure of a FOXO1 peptide in complex with 14-3-3 σ at 2.3 Å resolution revealed that this is a consequence of both steric hindrance and electrostatic repulsion. Furthermore, we found that AMPK-mediated Ser22 phosphorylation impairs Thr24 phosphorylation by AKT in a hierarchical manner. Thus, numerous mechanisms maintain FOXO1 activity via AMPK signaling. AMPK-mediated Ser22 phosphorylation directly and indirectly averts binding of 14-3-3 proteins, whereas phosphorylation of Ser383 and Thr649 complementarily stimulates FOXO1 activity. Our results shed light on a mechanism that integrates inputs from both AMPK and AKT signaling pathways in a small motif to fine-tune FOXO1 transcriptional activity.

Författare

Maria Saline

AstraZeneca AB

Lukas Badertscher

AstraZeneca AB

Madita Wolter

Technische Universiteit Eindhoven

Roxanne Lau

Technische Universiteit Eindhoven

Anders Gunnarsson

AstraZeneca AB

Tomas Jacso

Nuevolution A/S

AstraZeneca AB

Tyrrell Norris

AstraZeneca AB

Christian Ottmann

Technische Universiteit Eindhoven

Arjan Snijder

AstraZeneca AB

Journal of Biological Chemistry

0021-9258 (ISSN) 1083-351X (eISSN)

Vol. 294 35 13106-13116

Ämneskategorier

Cellbiologi

Biokemi och molekylärbiologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1074/jbc.RA119.008649

PubMed

31308176

Mer information

Senast uppdaterat

2019-11-08