Protein kinase Cα regulates the nucleocytoplasmic shuttling of KRIT1.
Cerebral cavernous malformation
KRIT1
Nucleocytoplasmic shuttling
PKC signaling
PKCα
PKCδ
Phorbol esters
Phosphoproteomics
Redox signaling
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
04 02 2021
04 02 2021
Historique:
received:
16
06
2020
accepted:
15
12
2020
pubmed:
15
1
2021
medline:
13
7
2021
entrez:
14
1
2021
Statut:
epublish
Résumé
KRIT1 is a scaffolding protein that regulates multiple molecular mechanisms, including cell-cell and 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 this process. 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 physiopathological functions of this protein.
Identifiants
pubmed: 33443102
pii: jcs.250217
doi: 10.1242/jcs.250217
pmc: PMC7875496
pii:
doi:
Substances chimiques
KRIT1 Protein
0
KRIT1 protein, human
0
Protein Kinase C-alpha
EC 2.7.11.13
Tetradecanoylphorbol Acetate
NI40JAQ945
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL117885
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141131
Pays : United States
Informations de copyright
© 2021. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing or financial interests.
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