Toll-like receptors stimulate regulated intramembrane proteolysis of the CSF-1 receptor through Erk activation.

The CSF-1 receptor is a protein-tyrosine kinase that regulates the renewal, differentiation and activation of monocytes and macrophages. We have recently shown that the CSF-1 receptor undergoes regulated intramembrane proteolysis, or RIPping. Here, we report that RIPping can be observed in response to pathogen-associated molecules, which act through Toll-like receptors (TLRs). TLR-induced CSF-1 receptor RIPping is largely independent of protein kinase C, while maximal RIPping depends on Erk activation. Our studies show that CSF-1 receptor RIPping can be activated by various intracellular signal transduction pathways and that RIPping is likely to play an important role during macrophage activation.