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STK 38 kinase acts as XPO 1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes
Author(s) -
Martin Alexandre PJ,
Jacquemyn Maarten,
Lipecka Joanna,
Chhuon Cerina,
Aushev Vasily N,
Meunier Brigitte,
Singh Manish K,
Carpi Nicolas,
Piel Matthieu,
Codogno Patrice,
Hergovich Alexander,
Parrini Maria Carla,
Zalcman Gerard,
Guerrera Ida Chiara,
Daelemans Dirk,
Camonis Jacques H
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948150
Subject(s) - nuclear export signal , microbiology and biotechnology , nuclear transport , phosphorylation , autophagy , biology , kinase , nuclear protein , hippo signaling pathway , activator (genetics) , effector , serine , context (archaeology) , cytoplasm , cell nucleus , transcription factor , biochemistry , gene , apoptosis , paleontology
Abstract STK 38 (also known as NDR 1) is a Hippo pathway serine/threonine protein kinase with multifarious functions in normal and cancer cells. Using a context‐dependent proximity‐labeling assay, we identify more than 250 partners of STK 38 and find that STK 38 modulates its partnership depending on the cellular context by increasing its association with cytoplasmic proteins upon nutrient starvation‐induced autophagy and with nuclear ones during ECM detachment. We show that STK 38 shuttles between the nucleus and the cytoplasm and that its nuclear exit depends on both XPO 1 (aka exportin‐1, CRM 1) and STK 38 kinase activity. We further uncover that STK 38 modulates XPO 1 export activity by phosphorylating XPO 1 on serine 1055, thus regulating its own nuclear exit. We expand our model to other cellular contexts by discovering that XPO 1 phosphorylation by STK 38 regulates also the nuclear exit of Beclin1 and YAP 1, key regulator of autophagy and transcriptional effector, respectively. Collectively, our results reveal STK 38 as an activator of XPO 1, behaving as a gatekeeper of nuclear export. These observations establish a novel mechanism of XPO 1‐dependent cargo export regulation by phosphorylation of XPO 1's C‐terminal auto‐inhibitory domain.