De Luca E(1)(2)(3), Perrelli A(4)(2), Swamy H(5), Nitti M(6), Passalacqua M(6), Furfaro AL(6), Salzano AM(7), Scaloni A(7), Glading AJ(8), Retta SF(1)(2). Author information:
(1)Department of Clinical and Biological Sciences, University of Torino, 10043
Orbassano, Torino, Italy [Email]
[Email] [Email]
(2)CCM Italia Research Network, National Coordination Center at the Department
of Clinical and Biological Sciences, University of Torino, 10043 Orbassano,
Torino, Italy.
(3)Center for Biomolecular Nanotechnologies, Istituto Italiano di Tecnologia,
73010 Arnesano, Lecce, Italy.
(4)Department of Clinical and Biological Sciences, University of Torino, 10043
Orbassano, Torino, Italy.
(5)Department of Pharmacology and Physiology, University of Rochester,
Rochester, NY 14642, USA.
(6)Department of Experimental Medicine, University of Genoa, 16132 Genova,
Italy.
(7)Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council,
80147 Napoli, Italy.
(8)Department of Pharmacology and Physiology, University of Rochester,
Rochester, NY 14642, USA [Email]
[Email] [Email]
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.
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