Cell signalling pathway regulation by RanBPM: molecular insights and disease implications

Abstract

RanBPM (Ran-binding protein M, also called RanBP9) is an evolutionarily conserved, ubiquitous protein which localizes to both nucleus and cytoplasm. RanBPM has been implicated in the regulation of a number of signalling pathways to regulate several cellular processes such as apoptosis, cell adhesion, migration as well as transcription, and plays a critical role during development. In addition, RanBPM has been shown to regulate pathways implicated in cancer and Alzheimer's disease, implying that RanBPM has important functions in both normal and pathological development. While its functions in these processes are still poorly understood, RanBPM has been identified as a component of a large complex, termed the CTLH (C-terminal to LisH) complex. The yeast homologue of this complex functions as an E3 ubiquitin ligase that targets enzymes of the gluconeogenesis pathway. While the CTLH complex E3 ubiquitin ligase activity and substrates still remain to be characterized, the high level of conservation between the complexes in yeast and mammals infers that the CTLH complex could also serve to promote the degradation of specific substrates through ubiquitination, therefore suggesting the possibility that RanBPM's various functions may be mediated through the activity of the CTLH complex.

Keywords: Alzheimer disease; CTLH complex; Gid; RanBPM; cancer.

Figure 1.

(a) Schematic diagram of full-length wild-type RanBPM. The conserved domains are SPRY (Sp1a kinase and ryanodine receptor), LisH (lissencephaly type-1-like homology), CTLH (C-terminal to LisH) and the C terminal CRA (CT-11-RanBPM). Figure adapted from [4,5]. (b) Predicted three-dimensional structure of RanBPM. The conserved domains, SPRY, LisH, CTLH and CRA domains, are shown in light-blue, light-pink, violet and hot-pink, respectively. Structure prediction was performed by the RaptorX Structure Prediction server [–9].

Figure 2.

(a) Tissue distribution of RanBPM mutations retrieved from the ICGC database. Figure adapted from the ICGC database [103]. (b) (i) Relative abundance of substitution mutations in RanBPM. (ii) Histogram indicating the position of somatic mutations in RanBPM. Figures adapted from the COSMIC database [104]. Frequency of RanBPM mutations in the COSMIC database is 0.43%.

Figure 3.

Proposed model of the topology of the mammalian CTLH complex. The model is adapted from that of the yeast GID complex described in Menssen et al. [127] as the topology of the mammalian complex has not been elucidated. The stoichiometry of the complex is not known. WDR26 association with the complex remains to be formally demonstrated.