Phosphorylation and the Cajal body: modification in search of function

Abstract

The Cajal body (CB) is a subnuclear domain that contains proteins and factors involved in a diverse range of activities including ribonucleoprotein maturation, histone gene transcription and telomerase assembly. Among these activities, the CBs' role in small nuclear ribonucleoprotein (snRNP) biogenesis is best characterized. Although CBs are found in plants, flies and mammals, not all cell types contain CBs. Rather, CBs are most prominent in transcriptionally active cells, such as cancer and neuronal cells. Many CB components, including the CB marker protein coilin, are phosphorylated in humans. The functional consequence of phosphorylation on CB assembly, activity and disassembly is largely unknown. Also unknown are the signaling pathways, kinases and phosphatases that act upon proteins which localize in the CB. The goal of this review is to demonstrate the need for a concerted effort towards elucidating the functional consequence of phosphorylation on CB formation and activity.

Fig. 1

Phosphorylation of coilin's C-terminus may help disengage the SMN complex from the CB and compete Sm proteins away from SMN. Data from [47] demonstrate that a coilin C-terminal fragment (amino acids 362-576) recovers more SmB′ in a pulldown assay when this fragment contains phosphomimic mutations compared to that bound to the wild-type fragment. In contrast, SMN binding to the phosphomimic coilin fragment is reduced compared to that recovered by the wild-type fragment. Based on this and other data reported in [47], the following model is proposed. In the CB, coilin may exist in two phosphoisoforms, one of which contains additional phosphorylated residues in the region of coilin that interacts with SMN (the RG box) and Sm proteins. Upon delivery of nascent snRNPs to the CB by the SMN complex, interactions between SMN and hypophosphorylated coilin (on left) displace snRNPs from the SMN complex. Released snRNPs can then bind hyperphosphorylated coilin (on right), allowing for snRNA modifications. Coilin phosphorylation by a kinase may promote SMN release from the CB, while phosphatase activity would release snRNPs. This mechanism may coordinate snRNP flux within the CB.