The master regulator of the macrophage development, differentiation, proliferation, survival, phagocytosis, cytokine secretion, motility, adhesion, migration, and spreading is the receptor tyrosine kinase (RTK) colony stimulating factor-1 receptor (CSF-1R). Aberrant CSF-1R signaling is present amongst a variety of highly prevalent and devastating human diseases in the United States such as atherosclerosis, cancer, inflammatory bowel disease, arthritis, and neuro-demyelination/neuro-degeneration. A better understanding of basic mechanisms that govern macrophage development and function is of vital importance in treating patients afflicted with these conditions/diseases. CSF-1R presentation on the macrophage cell surface is a required precursor for CSF1- induced RTK dimerization (activation) and downstream CSF-1R signaling cascades. Mechanisms which regulate CSF-1R trafficking are unstudied and mechanisms of RTK trafficking regulation are poorly understood. The evolutionarily conserved C-terminal Eps15 Homology Domain (EHD) protein family consists of vesicular trafficking regulating proteins. However, the role of EHD proteins in CSF-1R trafficking and signaling has not been studied. I have utilized primary (non-immortalized) murine/mammalian macrophages under inducible Ehd1 gene deletion/knockout (EHD1-KO) to explore the role of EHD1 in CSF-1R trafficking in macrophages. I have discovered an entirely novel function for EHD1 in anterograde transport and presentation of CSF-1R on the macrophage cell surface. EHD1-KO macrophages have significantly depleted total and surface CSF-1R expression (i.e. receptor available for ligand-binding and subsequently CSF-1R activation/signaling) when compared with control macrophages. In EHD1-KO macrophages, newly synthesized CSF-1R en route to the cell surface is essentially shunted to the lysosome and degraded. These findings reveal an entirely novel and essential role for EHD1 in anterograde transport/presentation of CSF-1R to the macrophage cell surface
