AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice

Abstract

ASK1-interacting protein-1 (AIP1), a recently identified member of the Ras GTPase-activating protein family, is highly expressed in vascular ECs and regulates EC apoptosis in vitro. However, its function in vivo has not been established. To study this, we generated AIP1-deficient mice (KO mice). Although these mice showed no obvious defects in vascular development, they exhibited dramatically enhanced angiogenesis in 2 models of inflammatory angiogenesis. In one of these models, the enhanced angiogenesis observed in the KO mice was associated with increased VEGF-VEGFR2 signaling. Consistent with this, VEGF-induced ear, cornea, and retina neovascularization were greatly augmented in KO mice and the enhanced retinal angiogenesis was markedly diminished by overexpression of AIP1. In vitro, VEGF-induced EC migration was inhibited by AIP1 overexpression, whereas it was augmented by both AIP1 knockout and knockdown, with the enhanced EC migration caused by AIP1 knockdown being associated with increased VEGFR2 signaling. We present mechanistic data that suggest AIP1 is recruited to the VEGFR2-PI3K complex, binding to both VEGFR2 and PI3K p85, at a late phase of the VEGF response, and that this leads to inhibition of VEGFR2 signaling. Taken together, our data demonstrate that AIP1 functions as an endogenous inhibitor in VEGFR2-mediated adaptive angiogenesis in mice.

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

“…3 However, DAB2IP knockout (KO) mice are viable and develop normally, arguing against a major role of this protein in embryogenesis and differentiation. 4,5 Regarding its mechanism of action, DAB2IP has an enzymatic activity whose core lies in the Ras-GAP domain. In addition, DAB2IP acts as an adaptor, or scaffold, in protein complexes relevant for signal transduction, and it can function as a competitor, or scavenger, by binding signaling proteins and preventing their interaction with upstream activators, or downstream effectors (Table 1).…”

“…10,11 Interestingly, animal models showed that DAB2IP functions as endogenous inhibitor of adaptive angiogenesis in part by binding directly to VEGFR-2 and limiting PI3K activation ( Figure 4b). 4 GSK3β-β-catenin signaling. GSK3β is a ser/thr kinase that phosphorylates numerous substrates, often triggering their degradation.…”

“…However, these animals have phenotypes related to cancer formation or progression, such as increased proliferation of the prostate epithelium, 37 dysplasia of the colon epithelium, 38 and augmented inflammatory angiogenesis. 39 Therefore, loss of DAB2IP may not be sufficient to induce cancer formation, but can unleash the oncogenic potential of multiple extracellular signals, promoting tumor progression and aggressiveness.…”

“…25 In endothelial cells, DAB2IP interacts with the cytoplasmic domain of VEGFR-2 counteracting VEGF-induced signal transduction. 4 (c) WNT/GSK3β/β-catenin signaling. DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation.…”

“…Indeed, DAB2IP − / − mice show enhanced inflammation in models of ischemic hind limb, graft arteriosclerosis, and inflammatory angiogenesis. 4,33,34,54 In hyperlipidemic ApoE − / − mice, DAB2IP KO increases secretion of inflammatory cytokines and augments macrophage infiltration, thereby inducing endothelial dysfunction and early phases of atherosclerosis. 54 Notably, vascular endothelial-specific depletion of DAB2IP promotes tumor growth and dissemination in melanoma and breast cancer mouse models, favoring establishment of a prometastatic microenvironment.…”