FAK in the nucleus prevents VSMC proliferation by promoting p27 and p21 expression via Skp2 degradation
| Autor: | James M. Murphy, Eun-Young Erin Ahn, Ssang-Taek Lim, Kyuho Jeong |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
0301 basic medicine Physiology Cell 030204 cardiovascular system & hematology Muscle Smooth Vascular Focal adhesion 03 medical and health sciences 0302 clinical medicine Cyclin D1 Cyclin-dependent kinase Physiology (medical) SKP2 medicine S-Phase Kinase-Associated Proteins Cells Cultured Cell Proliferation biology Kinase Chemistry Original Articles Cell cycle Ubiquitin ligase Cell biology 030104 developmental biology medicine.anatomical_structure Focal Adhesion Protein-Tyrosine Kinases cardiovascular system biology.protein biological phenomena cell phenomena and immunity Cardiology and Cardiovascular Medicine Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | Cardiovasc Res |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvab132 |
| Popis: | Aim Vascular smooth muscle cells (VSMCs) normally exhibit a very low proliferative rate. Vessel injury triggers VSMC proliferation, in part, through focal adhesion kinase (FAK) activation, which increases transcription of cyclin D1, a key activator for cell cycle-dependent kinases (CDKs). At the same time, we also observe that FAK regulates the expression of the CDK inhibitors (CDKIs) p27 and p21. However, the mechanism of how FAK controls CDKIs in cell cycle progression is not fully understood. Methods and results We found that pharmacological and genetic FAK inhibition increased p27 and p21 by reducing stability of S-phase kinase-associated protein 2 (Skp2), which targets the CDKIs for degradation. FAK N-terminal domain interacts with Skp2 and an APC/C E3 ligase activator, fizzy-related 1 (Fzr1) in the nucleus, which promotes ubiquitination and degradation of both Skp2 and Fzr1. Notably, overexpression of cyclin D1 alone failed to promote proliferation of genetic FAK kinase-dead (KD) VSMCs, suggesting that the FAK-Skp2-CDKI signaling axis is distinct from the FAK-cyclin D1 pathway. However, overexpression of both cyclin D1 and Skp2 enables proliferation of FAK-KD VSMCs, implicating that FAK ought to control both activating and inhibitory switches for CDKs. In vivo, wire injury activates FAK in the cytosol and increased Skp2 and decreased p27 and p21 levels. Conclusions Both pharmacological FAK and genetic FAK inhibition reduced Skp2 expression in VSMCs upon injury, which significantly reduced intimal hyperplasia through elevated expression of p27 and p21. This study revealed that nuclear FAK-Skp2-CDKI signaling negatively regulates CDK activity in VSMC proliferation. Translational perspective Increased VSMC proliferation contributes to pathological vessel narrowing in atherosclerosisand following vascular interventions. Blocking VSMC proliferation will reduce atherosclerosisprogression and increase patency of vascular interventions. We found that forced nuclear FAKlocalization by FAK inhibition reduced VSMC proliferation upon vessel injury. Nuclear FAKdecreased Skp2 protein expression by proteasomal degradation, thereby increasing theexpression of cell cycle inhibitors p27 and p21 and blocking cell cycle progression. This studyhas demonstrated the potential for FAK inhibitors in blocking VSMC proliferation to treat vessel narrowing diseases. |
| Databáze: | OpenAIRE |
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