Protein kinase C alpha regulates the nucleocytoplasmic shuttling of KRIT1
Autor: | Andrea Scaloni, Elisa De Luca, Harsha Swamy, Anna Lisa Furfaro, Andrea Perrelli, Anna Maria Salzano, Angela Glading, Mariapaola Nitti, Mario Passalacqua, Saverio Francesco Retta |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Scaffold protein
CCM1/KRIT1 Cerebral Cavernous Malformation (CCM) Nucleocytoplasmic shuttling PKC signaling PKCα PKCδ Phorbol esters Phosphoproteomics Redox signaling Protein Kinase C-alpha KRIT1 Regulator Active Transport Cell Nucleus PKC alpha Biology PKC delta Biochemistry 03 medical and health sciences 0302 clinical medicine Physiology (medical) Gene silencing Humans Phosphorylation Protein kinase A KRIT1 Protein Protein kinase C Cerebral cavernous malformation HeLa Cells Tetradecanoylphorbol Acetate 030304 developmental biology Cell Nucleus 0303 health sciences Cell Biology Active Transport Cell biology Cytoplasm 030217 neurology & neurosurgery Research Article |
Zdroj: | Journal of cell science 134 (2021). doi:10.1242/jcs.250217 info:cnr-pdr/source/autori:Elisa De Luca, Andrea Perrelli, Harsha Swamy, Mariapaola Nitti, Mario Passalacqua, Anna Lisa Furfaro, Anna Maria Salzano, Andrea Scaloni, Angela J. Glading, Saverio Francesco Retta/titolo:Protein kinase C alpha regulates the nucleocytoplasmic shuttling of KRIT1/doi:10.1242%2Fjcs.250217/rivista:Journal of cell science/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:134 Journal of Cell Science article-version (VoR) Version of Record |
Popis: | 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. Summary: A novel role for PKC signaling in triggering Ser/Thr phosphorylation and regulating nucleocytoplasmic shuttling of KRIT1, a major protein with pleiotropic functions associated with human diseases. |
Databáze: | OpenAIRE |
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