Regulation of EGF receptor trafficking fate by phosphorylation and Odin

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Binding of growth factors to receptors is a key mechanism that regulates the growth and development of metazoans. Epidermal growth factor receptor (EGFR) is a prototypical growth factor receptor. Activated EGFR is rapidly internalization by endocytosis. Internalized EGFR either recycle back to the cell surface or degrade in lysosomes as a consequence of a trafficking sorting switch. EGFR also internalize and recycle in response to cellular stresses. These processes control receptor density at the cell surface, and in turn signaling responses to diverse ligand concentration gradients and environmental cues, which are highly variable in metazoans.Our long term objective is to understand in quantitative mechanistic terms, how dynamic covalent modifications and protein interactions control the trafficking fate of growth factor receptors.***We discovered EGFR phosphorylations (Y998, S1039) and the protein Odin as factors affecting EGFR trafficking. For example, failure to phosphorylate activated EGFR at Y998 causes recycling, whereas cells without Odin lack EGFR recycling. Regulation of receptor trafficking has been intensively studied, but molecular mechanistic details of how EGFR phosphorylation regulates its recycle-or-degrade trafficking fate are not known. Our near term objective is to determine the molecular mechanism of phosphorylation-mediated EGFR sorting that constitutes a recycle-or-degrade switch.***To achieve this, we propose the following specific aims:***Aim 1: Address questions that test Odin's role in EGFR recycling: (A) Does Odin bind Y998 for recycling, but not pY998, which stimulates degradation? (B) Does Odin function in stress-induced EGFR recycling? (C) Does phosphorylation of Odin modulate its interaction with EGFR?***Aim2: Test if EGFR-S1039 phosphorylation controls EGFR recycling, and prevents transport to the lysosome. (A) Is S1039 required for EGFR recycling? (B) Does a receptor-associated phosphatase modulate S1039 phosphorylation, and consequently EGFR recycling? (C) Determination of temporal and spatial regulation of EGFR-S1039 phosphorylation towards defining its role in recycling.***A mechanistic understanding phosphorylation/Odin-mediated EGFR sorting will lead to future studies of how receptor trafficking modulates growth factor and environmental signals in complex organisms. This program will also contribute to the training of HQP in the fields of molecular and cell biology, and proteomics.**