Kinase cut-and-run

Cell 157, 1061–1072 (2014)

TRPM7, an essential cation-conducting channel that is involved in embryonic development, is unusual in having a C-terminal serine/threonine kinase domain with an unknown function. A new study by Krapivinsky et al. now reveals that the kinase domain is cleaved from the membrane channel and acts in the nucleus by phosphorylation of chromatin proteins. Examination of the expression levels of TRPM7 across cell and tissue types identified specific proteolytic fragments of TRPM7 that were localized to the nuclei of cells and contained an active kinase domain (M7CK). Affinity purification and co-immunoprecipitation revealed that M7CKs bind to but do not appear to phosphorylate several nuclear proteins involved in chromatin remodeling, including RYBP, a zinc-finger protein. These M7CK–chromatin protein complexes lead to phosphorylation of Ser10 of histone H3 (H3S10p), either directly or in concert with other kinases. H3S10p modification perturbs the abundance of other histone marks and leads to specific regulation of TRPM7-responsive genes. To relate channel function to this nuclear role of M7CKs, the authors showed that TRPM7 actively increases cytoplasmic Zn²⁺ concentrations and that M7CK binding to RYBP and other zinc finger–containing proteins was Zn²⁺ dependent. Though the proteases involved in M7CK release remain uncharacterized and may vary by cell type, the current study suggests a new mechanism to transmit ion channel signals at the membrane to rapid changes in gene expression in the nucleus.