The multifaceted PDCD10/CCM3 gene

Abstract

The programmed cell death 10 (PDCD10) gene was originally identified as an apoptosis-related gene, although it is now usually known as CCM3, as the third causative gene of cerebral cavernous malformation (CCM). CCM is a neurovascular disease that is characterized by vascular malformations and is associated with headaches, seizures, focal neurological deficits, and cerebral hemorrhage. The PDCD10/CCM3 protein has multiple subcellular localizations and interacts with several multi-protein complexes and signaling pathways. Thus PDCD10/CCM3 governs many cellular functions, which include cell-to-cell junctions and cytoskeleton organization, cell proliferation and apoptosis, and exocytosis and angiogenesis. Given its central role in the maintenance of homeostasis of the cell, dysregulation of PDCD10/CCM3 can result in a wide range of altered cell functions. This can lead to severe diseases, including CCM, cognitive disability, and several types of cancers. Here, we review the multifaceted roles of PDCD10/CCM3 in physiology and pathology, with a focus on its functions beyond CCM.

Keywords: CCM, cerebral cavernous malformation; CNS, central nervous system; CSC, CCM signaling complex; Cancer; Cell signaling; Cell-cycle; ECs, endothelial cells; GBM, glioblastoma multiforme; NVU, neurovascular unit; Neurovascular unit; PDCD10/CCM3; VEGF, vascular-endothelial growth factor.

Figure 1

Structure and interactions of PDCD10/CCM3. (A) Schematic representation of the PDCD10/CCM3 domains and its interactors. The PDCD10/CCM3 dimerization domain at the N-terminal has four α-helices (green, α A-D) as well as the FAT-homology domain at the carboxy-terminal (yellow, α F–I), as shown. The different interactors that are responsible for the functions of PDCD10/CCM3 are listed under their relative domains. (B) Overview of the CCM signaling complex structure and its localization, interactions and functions under wild-type and PDCD10/CCM3-null conditions. (C) Beyond the CSC, PDCD10/CCM3 is a STRIPAK component and stabilizes GCKIII kinases through the binding to GM130, a Golgi-resident protein. Loss of PDCD10/CCM3 leads to GCKIII kinases destabilization together with an impaired cell migration and a dysregulated neutrophil exocytosis.

Figure 2

PDCD10/CCM3 regulates the cell-cycle. (A) Under physiological condition the cell cycle is tightly regulated: the cells enter into senescence after an excessive number of in vitro cell doublings or into apoptosis in response to stressful events such as elevated levels of ROS species or low levels of serum. (B) PDCD10/CCM3 is a pivotal regulator of these events as its depletion leads to impaired entrance into senescence (G1 phase – green arrow) and apoptosis. In addition, the loss of PDCD10/CCM3 alters the proliferative behavior of the cell driving its aberrant entrance into S phase (S phase – green arrow).

Figure 3

Cell-autonomous and non-autonomous roles of PDCD10/CCM3 within the neurovascular unit. (A) PDCD10/CCM3 plays multiple roles across the different components of the neurovascular unit and controls the proper formation of blood vessels and the maturation of neurons. (B) Depletion of PDCD10/CCM3 in neural cells causes an increased brain size and an impaired neurite growth in neurons (D), highlighting a cell-autonomous role. (C) PDCD10/CCM3 neural loss gives rise to cerebrovascular lesions, suggesting a non-autonomous cellular effect within the cerebral vasculature. (E) PDCD10/CCM3 has a major role during the regulation of radial migration, a process taking place in the cerebral cortex where neurons migrate along radial glia guides from the ventricular (VZ) to the marginal zone (MZ). (F) Loss of PDCD10/CCM3 in radial glia causes both cell autonomous and non-autonomous effects, respectively, and an impaired development of radial glia processes and altered migration and morphology of the neurons.

Figure 4

PDCD10/CCM3 expression in cancer and its regulation by mi-RNAs. (A) Under physiological conditions PDCD10/CCM3 is epigenetically-regulated by different mi-RNAs, while in cancer, mi-RNAs can act either as enhancers or silencers in a context-dependent manner, giving rise to different pathological conditions. (B) The context-dependent correlations between expression of PDCD10/CCM3 and the indicated mi-RNA regulators are shown, along with their associated pathological phenotypes.