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Receptor tyrosine kinases (RTKs) are crucial regulators of cellular processes, including growth, differentiation, and survival. They function by transmitting extracellular signals through membrane receptors to intracellular signaling pathways. Among these RTKs, the platelet-derived growth factor receptors (PDGFRs) and the epidermal growth factor receptor (EGFR) are vital for maintaining cellular homeostasis and are implicated in various pathological conditions, including cancer. In addition to these pathways, nuclear receptors such as the vitamin D receptor (VDR) also play a significant role in modulating cellular functions. The VDR regulates gene expression in response to the active form of vitamin D, and its cross-talk with RTK pathways offers a complex layer of regulatory control that affects cellular proliferation and differentiation.

This thesis investigates the complex signaling mechanisms of PDGFRs and EGFR, emphasizing the influence of lipid rafts, Rho GTPases, and cross-talk with vitamin D receptor (VDR) signaling.

Paper I focuses on the consequences of lipid raft disruption on PDGFR-β signaling. The research highlights that disrupting lipid rafts alters the association of PDGFR-β with some of its downstream signaling components, reducing the activity of ERK1/2 and AKT in BJ-hTERT fibroblasts and AKT and Src in U2OS osteosarcoma cells. 

Paper II explores the differential impact of cholesterol depletion on EGFR and PDGFR-β signaling. We found that EGFR and PDGFR-β internalize into distinct compartments after activation, converging only after prolonged stimulation. Cholesterol depletion enhanced EGFR dimerization and activation while reducing downstream AKT and ERK1/2 phosphorylation, suggesting distinct membrane microdomain dependencies for these receptors.

Paper III explores the impact of Rho GTPase depletion on the phosphorylation and internalization of PDGFR-α and -β. The findißngs suggest that the depletion of Cdc42, Rac1, or RhoA significantly diminishes PDGFR phosphorylation, and downstream stability of STAT1 and activation of STAT1 and STAT3 indicating that these Rho GTPases are integral for the optimal signaling of PDGFRs.

Paper IV examines the cross-talk between VDR and RTK signaling. We discovered that EGF, but not PDGF-BB, enhances VDR-mediated CYP24A1 expression, indicating a selective interaction between these pathways. Additionally, 1,25(OH)2-vitamin D₃ inhibited PDGF-BB-induced proliferation and PDGFR-β phosphorylation, revealing a complex interplay.

Collectively, these studies elucidate the nuanced regulatory mechanisms of PDGFRs and EGFR, emphasizing the roles of lipid rafts, Rho GTPases, and cross-talk with nuclear receptors.