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Protein Kinase Cα (Pkcα) Regulates the Nucleocytoplasmic Shuttling of KRIT1
Author(s) -
Glading Angela,
De Luca Elisa,
Perrelli Andrea,
Swamy Harsha,
Nitti Mariapaola,
Passalacqua Mario,
Furfaro Anna Lisa,
Salzano Anna Maria,
Scaloni Andrea,
Retta Saverio Francesco
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04269
Subject(s) - protein kinase c , microbiology and biotechnology , cytoplasm , nuclear localization sequence , scaffold protein , subcellular localization , signal transduction , chemistry , gene silencing , kinase , biology , biochemistry , gene
KRIT1 is a scaffolding protein that regulates endothelial barrier function, endothelial cell‐matrix adhesion, and redox homeostasis and signaling. However, rather little is known about how KRIT1 is itself regulated. KRIT1 is found in both the cytoplasm and the nucleus, yet the upstream signaling proteins and mechanisms that regulate KRIT1 nucleocytoplasmic shuttling are not well understood. Here, we identify a key role for protein kinase C (PKC). In particular, we found that PKC activation promotes the redox‐dependent cytoplasmic localization of KRIT1, whereas inhibition of PKC or treatment with the antioxidant N‐acetylcysteine leads to KRIT1 nuclear accumulation. Moreover, we demonstrated that the N‐terminal region of KRIT1 is crucial for the ability of PKC to regulate KRIT1 nucleocytoplasmic shuttling, and may be a target for PKC‐dependent regulatory phosphorylation events. Finally, we found that silencing of PKCα, but not PKCδ, inhibits phorbol‐12‐myristate‐13‐acetate (PMA)‐induced cytoplasmic enrichment of KRIT1, suggesting a major role for PKCα in regulating KRIT1 nucleocytoplasmic shuttling. Overall, our findings identify PKCα as a novel regulator of KRIT1 subcellular compartmentalization, thus shedding new light on the physiological and pathological functions of this protein.