Jeong K, Murphy JM, Erin Ahn EY, Steve Lim ST

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 ...

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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.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.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.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.

Date: Apr. 11, 2021

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