Regulation of EGFR-mediated cell signaling and EGFR endocytosis during mitosis and other phases of cell cycle

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The epidermal growth factor receptor (EGFR), like other receptor tyrosine kinases (RTKs), regulates key events in cell growth, differentiation, survival and migration. Aberrant signaling from EGFR has been implicated in many diseases. EGFR activation stimulates various signaling pathways that regulate multiple cell functions. The binding of EGF to EGFR also stimulates the rapid internalization of EGFR. EGFR endocytosis and EGFR-mediated cell signaling are mutually regulated. EGF stimulates cell proliferation by driving the cell cycle, which is comprised of four phases: G1, S, G2 and M. ******In spite of significant advances in our understanding of EGFR signaling and trafficking, some critical knowledge is still lacking. To date, the study of receptor signaling and endocytosis has largely been done assuming cellular homogeneity. The heterogeneity of receptor signaling and endocytosis has been rarely explored. In our previous research, we studied the heterogeneity of EGFR signaling from different subcellular locations along its endocytic trafficking pathway. In this proposal, we seek to explore the heterogeneity of EGFR signaling among various phases of cell cycle. ******Our current knowledge of EGFR signaling and EGFR endocytosis comes mostly from the studies of cells in G1 phase of the cell cycle. Very little is known regarding EGFR-mediated signaling and endocytosis in S, G2 and M phases.*Recently, we have studied EGF-induced EGFR signaling and endocytosis during mitosis and have obtained some interesting results. Contrary to dogma, we have shown that in mitosis, EGF does activate EGFR and selectively activates some downstream signaling proteins (such as Akt2, Cbl and PLC-γ1), while avoiding others (such as Akt1 and ERK). In addition, we have found that in mitosis, EGF-induced EGFR endocytosis does not cease, but is regulated differently from interphase. Our preliminary data also suggest that EGFR signaling may be regulated differently during S and G2 phases of the cell cycle. Therefore, we propose that EGFR endocytosis and EGFR-mediated cell signaling are regulated differently in each phase of cell cycle to provide cellular heterogeneity and specifically serve the special needs of the cell in each cell cycle phase. We plan to test our hypothesis with the following aims:*******Aim 1. To study the regulation of EGFR signaling in mitosis****Aim 2. To study EGFR endocytosis and its effect on EGFR-mediated cell signaling in mitosis****Aim 3. Map the regulation of EGFR-mediated cell signaling in S, G2 and mitotic subphases*******The long-term goal of our research program is to use EGFR as a model system to explore the regulation of cellular heterogeneity of RTK signaling and the biological significance of this cellular heterogeneity. Our findings with EGFR may well apply to other RTKs in diverse cell types, which will significantly advance our fundamental knowledge regarding cell regulation.******