Graduation Date

Summer 8-19-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Hamid Band M.D., Ph.D.

Abstract

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.

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