Novel functions of CCM1 delimit the relationship of PTB/PH domains

Abstract

The study provides new insight into the structural characteristics of PTB/PH domains, essential structural elements of PTB/PH domain required for NPXY motif-binding, and function and relationship among PTB, PH and FERM domains.

Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers

“…CCM proteins have been demonstrated to play major roles in microvascular angiogenesis in human and animal models (1)(2)(3)(4)(5)(6), which is an essential step for cancer growth during tumorigenesis (5,6). Three genes have been identified as causes of CCMs: cerebral cavernous malformations 1 [(CCM1) also termed Krev interaction trapped 1 (KRIT1)], cerebral cavernous malformation 2 [(CCM2) also termed MGC4607] and cerebral cavernous malformation 3 [(CCM3) also termed programmed cell death 10 (PDCD10)].…”

“…As one of three key components of the CSC, CCM3 was initially identified as a tumor-associated apoptotic protein (7) which directly interacts with CCM2 within the CSC complex (8,9), suggesting that the CSC complex may be involved in tumorigenesis. CCM1 is ubiquitously expressed in various cells and tissues (5,10); likewise, almost all expressed isoforms of CCM2 are ubiquitously expressed in various cells and tissues (11), providing additional evidence for the potential involvement of the CSC in diverse cellular events in health and diseases, including cancer.…”

Comparative omics of CCM signaling complex (CSC)

“…It has been demonstrated that the three CCM proteins form the CSC, which plays an essential role in the pathogenesis of CCMs when disrupted [26]. Efforts to dissect CSC signaling cascades have been made (Additional file 11) [8,10,[20][21][22][23][24][25][26], but with some contradicting outcomes. It is essential to establish comparative omics methods to assess similarities among those independent studies, which can aid in identification of potential biomarker candidates for prognostic and diagnostic applications.…”

“…A comparative database in excel (Additional files 1 and 2) was set up for the nine total available CCM cohorts that were analyzed for our comparative omics studies [8,10,[19][20][21][22][23][24][25] (Fig. 1).…”

“…The CCM signaling complex (CSC), composed of all three CCM genes, interacts with numerous proteins and has affinity for a wide range of ligands, contributing to cellular processes including numerous angiogenic signaling cascades, adhesion, cell migration, and apoptotic pathways [7][8][9][10][11]. CCM proteins have been shown to be essential for angiogenic processes including new blood vessel development [12][13][14][15], blood vessel stability [16], vascular angiogenesis [9,17], cell adhesion to extracellular matrix, tube formation, and endothelial cell morphogenesis [14,18].…”