Maintenance of tissue homeostasis by receptor tyrosine kinase (RTK) and Jun-N-terminal kinase (JNK)

Abstract

Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biomedical Genetics, 2008. Maintenance of homeostasis is crucial for the development and survival of the multi-cellular organisms. Intrinsically, proper mitogenic and differentiation signals have to be accurately delivered for the cell to adopt the right cell fate. Extrinsically, as organisms are constantly challenged by environmental insults, damaged cells have to be either salvaged or sacrificed to keep the integrity of the whole organism. Thus, mechanisms that govern cell specification and/or correct/eliminate malfunctioned cells are expected to serve as safeguard for the body since such cells pose a threat to the organism by exhibiting uncontrolled proliferation, growth or cell death. Misregulation of these cellular behaviors is linked to the onset and progression of human diseases, notably cancer and neurodegenerative diseases. In the first part of our study, we have carried out experiments to demonstrate that JNK mediates an apoptotic response to remove UV-damaged tissues by upregulating the proapoptotic gene hid. This transcription-dependent apoptotic response relies on the cooperation of two downstream transcription factors, Fos and FoxO, on the hid regulatory sequence. Interestingly, we found that RTK signaling pathways antagonize the apoptotic response by inhibiting FoxO activity through their common downstream PI3K-Akt axis suggesting FoxO as an integrator of stress/survival signals regulating apoptosis according to cellular context. In the second part, we present evidence showing that the lipid-raft-associated proteins flotillin-1 and -2 influence cell function in response to stress as well as during development by differential regulation of EGFR and of Notch signaling. In flotillin mutant animals, cell proliferation and patterning are deficient, resulting in dramatic overgrowth phenotypes. Our results suggest that flotillins regulate EGFR/Notch signaling by targeting the receptors to endosomal compartments for possible activation, isolation or degradation. Since flotillins function to fine-tune the balance between EGFR and Notch and prevent excessive tissue growth, we propose that they are required to suppress transformation under normal conditions. This study has provided insights into the mechanisms of homeostasis during development and in response to genotoxic stresses. Our results contribute to a better understanding of tumorigenesis and degenerative diseases and would facilitate the discoveries of novel therapeutic targets for these pathologies in the future.