The CTLH Complex in Cancer Cell Plasticity

Abstract

Cancer cell plasticity is the ability of cancer cells to intermittently morph into different fittest phenotypic states. Due to the intrinsic capacity to change their composition and interactions, protein macromolecular complexes are the ideal instruments for transient transformation. This review focuses on a poorly studied mammalian macromolecular complex called the CTLH (carboxy-terminal to LisH) complex. Currently, this macrostructure includes 11 known members (ARMC8, GID4, GID8, MAEA, MKLN1, RMND5A, RMND5B, RANBP9, RANBP10, WDR26, and YPEL5) and it has been shown to have E3-ligase enzymatic activity. CTLH proteins have been linked to all fundamental biological processes including proliferation, survival, programmed cell death, cell adhesion, and migration. At molecular level, the complex seems to interact and intertwine with key signaling pathways such as the PI3-kinase, WNT, TGFβ, and NFκB, which are key to cancer cell plasticity. As a whole, the CTLH complex is overexpressed in the most prevalent types of cancer and may hold the key to unlock many of the biological secrets that allow cancer cells to thrive in harsh conditions and resist antineoplastic therapy.

Figure 1

Schematic representation of the 11 members of the mammalian CTLH complex. Except for ARMC8, GID4, and YPEL5, all the other members present a LisH domain followed by a defining CTLH domain. Both LisH and CTLH domains are considered protein-protein interaction domains. MAEA in association with RMND5A or RMND5B provides the E3-ligase enzymatic activity of the complex. RANBP9 and RANBP10 are collectively called Scorpins (Spry-COntaining Ran binding ProteINS).

Figure 2

Schematic representation of the CTLH complex. The mammalian CTLH complex is a heterodecameric multimolecular structure built on dimer of GID8 (DARK RED). Its core (RED) includes the heterodimer MAEA-RMND5A or MAEA-RMND5B that together provide the E3-ligase enzymatic activity, the Scorpins (RANBP9, RANBP10), and WDR26. Peripheral components (GREEN) are GID4, ARMC8, MKLN1, and YPEL5.

Figure 3

CTLH gene alterations in the most prevalent malignancies in the USA. The TCGA collection of the top 5 most prevalent malignancies in the USA reported in Table 2 was queried for alterations pertaining the 11 CTLH genes (http://www.cbioportal.org). (a) About 5% of cases show mutations of the CTLH genes. (b) For all the analyzed genes, the vast majority of mutations are missense and their functional significance is unknown. (c) 13% of cases show putative copy number variations (CNVs) of the CTLH genes. (d) Putative amplifications are overwhelmingly more prevalent than copy number losses of ARMC8, GID8, RMND5B, WDR26, and YPEL5. On the other hand, GID4, MAEA, and RANBP10 display more copy number losses than gains. (e) 61% of cases show alteration of expression concerning the CTLH genes. (f) Cases of overexpression are overwhelmingly more prevalent than underexpression with the exception of GID4.