CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

Abstract

CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis.

The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

“…Tip cells are located at the ends of angiogenic sprouts and their filopodial protrusions directed vessel growth toward angiogenic attractants 57 – 59 . Recent data showed that Cyr61 , a known YAP/TAZ target gene, stimulates tip cell proliferation and activity 60 . Therefore, loss of endothelial Wwc2 expression might activate YAP/TAZ-dependent Cyr61 expression that in turn leads to enhanced tip cell activity and disturbed vessel sprouting.…”

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

“…One possible alternative mechanism is through CCN protein upregulation, as this has been shown to induce ER-stress and UPR-activation in both stellate cells and hepatocytes by in vitro and in vivo approaches. CCN proteins are ECM-associated secreted proteins which play a role in a with a wide array of important functions, such as wound healing and tumorigenesis ( Park et al, 2019 ). Adenoviral CCN gene transfer and overexpression of CCN proteins have been shown to induce ER-stress-mediated stellate cell senescence and apoptosis in later stages of fibrosis, consequently contributing to fibrosis resolution ( Borkham-Kamphorst et al, 2016 ; Borkham-Kamphorst et al, 2018 ).…”

Role of Hippo-YAP Signaling in Osseointegration by Regulating Osteogenesis, Angiogenesis, and Osteoimmunology

“…The foreign-body reaction starts with layer of proteins that come from blood and interstitium immediately forming on the surface of biomaterial after implantation, which activates inflammatory reaction of related cells as a result (Wilson et al, 2005;Singhatanadgit et al, 2019). Researches on enhancing the biocompatibility of implant material have been a hot topic in dentistry, for instance, surface modification (Hamlet and Ivanovski, 2011;Hamlet et al, 2012;Palmquist et al, 2013;Fukuda et al, 2019). as well as changing the design and composition of implants (Cooper et al, 2016;Wang Y. et al, 2019) are generally proposed as available strategies.…”

“…Mechanistically, YAP/TAZ promotes migration of tip cells by activating CDC42 and facilitates the formation and junction of filopodia, an essential dynamic structure of tip cell that dominates its sprouting function, by promoting the remodeling of actin cytoskeleton ( Kim et al, 2017 ; Sakabe et al, 2017 ). Likewise, the identity of tip cells are induced by CCN1, through interaction with integrin αvβ3/VEGFR and activation of downstream Hippo pathway thus promoting nucleus translocation of YAP/TAZ, which coordinates CCN1 in turn as a positive feedback ( Park et al, 2019 ). While overactivating YAP/TAZ leads to pathologic sprouting pattern ( Astone et al, 2018 ).…”