So-called "two-component" regulatory systems are key signal transducers in prokaryotes, but there is little evidence for their function in higher eukaryotes. One mammalian protein that shows histidine kinase activity characteristic of sensor proteins in two-component systems is Nm23-H1, a member of a family of proteins that contribute to suppression of metastasis of tumor cells. Hartsough et al. searched for mammalian proteins with similarity to proteins known to function in a two-component regulatory system. In the plant Arabidopsis, a histidine sensor kinase interacts with the protein CTR1, which may function by inhibiting signaling through mitogen-activated protein kinase (MAPK) pathways. CTR1 turns out to have sequence similarity with the mammalian kinase suppressor of Ras (KSR) protein, which is thought to serve as a scaffolding protein for the MAPK pathway. Checking whether KSR might function in signaling via Nm23-H1, the authors found that KSR was detectable in immunoprecipitates of NM23-H1from MDA-MB-435 human breast carcinoma cells. Nm23-H1 also promoted phosphorylation of KSR on serine residues in vitro, an effect that was lost in mutants lacking the autophosphorylated histidine residue in Nm23-H1. In transfected cells, overexpresion of Nm23-H1 reduced MAPK activity (total activity of ERK1 and ERK2) to about half that in control cells, whereas expression of a kinase-deficient mutant of Nm23-H1 led to enhanced MAPK activity. Thus it is possible that, like CTR1 in plants, the related mammalian protein KSR might act to transmit signals mediated by histidine kinase activity to suppress MAPK activity.
M. T. Hartsough, D. K. Morrison, M. Salerno, D. Palmieri, T. Ouatas, M. Mair, J. Patrick, P. S. Steeg, Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway, J. Biol. Chem. 277, 32389-32399 (2002). [Abstract] [Full Text]