PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations

Abstract

Cerebral cavernous malformations (CCM) are common vascular malformation of the brain and are associated with abnormal angiogenesis. Although the exact etiology and the underlying molecular mechanism are still under investigation, recent advances in the identification of the mutations in three genes and their interactions with different signaling pathways have shed light on our understanding of CCM pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression. Here, we provide an update literature review on the current knowledge of the PTEN/PI3K/Akt/VEGF signaling in angiogenesis, more importantly in CCM pathogenesis. In addition to reviewing the current literatures, this article will also focus on the structural domain of the three CCM proteins and their interacting partners. Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment.

Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice

“…Our results identify an association between NgBR and CCM proteins in that loss of NgBR in endothelial cells shows less CCM1 and CCM2 proteins, which are involved in the pathogenesis of cerebral cavernous malformations (He et al, 2010; Kar et al, 2015). CCMs disease is a common form of vascular malformation with a prevalence of 0.1 to 0.5 % in the human population (Al-Shahi Salman et al, 2012; Draheim et al, 2014; Fischer et al, 2013; Haasdijk et al, 2012).…”

“…Given that CCM1/2/3 proteins have been identified as responsible for cerebral cavernous malformations (CCMs) (He et al, 2010; Kar et al, 2015), a brain blood vessel assembly defect, we investigated whether these proteins were attenuated in NgBR deficient endothelial cells. NgBR deficiency in EC decreases both transcriptional and translational levels of CCM1 and CCM2 in HBMEC determined by real-time PCR (Fig.…”

lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway

“…On the other hand, it exhibits an oncogenic role [40] by negatively regulating PTEN/PI3K/AKT pathway [41]. PTEN as a tumor suppressor is an antagonist regulator of the PI3K/AKT pathway, involved in the regulation of cerebral cavernous malformations [42]. Intriguingly, we discovered that miR-494 had the negative correlation with PTEN expression in HAs samples and exerted potential to bind with 3'UTR of PTEN.…”

PHACE syndrome is associated with intracranial cavernous malformations

“…Sporadic cases are most often solitary, while the familial variant is associated with multiple, scattered lesions and inherited in an autosomal dominant fashion [32]. Familial CCM is known to be associated with loss of function mutations in three genes that each plays a pivotal role in controlling signaling pathways responsible for cellular responses to oxidative stress [18,32,37], including KRIT1 [9], CCM2 [22], and PDCD10 [3]. It has been well documented that hypoxia plays a critical role in the formation of both sporadic and familial CCMs [27,35,39].…”

“…These lesions can present with acute or chronic symptoms, including headache, seizure, and/or neurologic deficit from hemorrhage, but the most CCMs are asymptomatic throughout the patient's lifetime and are discovered incidentally. The majority of CCMs occur sporadically, but as many as 20 % occur in a familial pattern [18]. CCMs can range in size and number and vary in their susceptibility to hemorrhage.…”