REGULATION OF TNF RECEPTOR SIGNALING AND FUNCTIONS

National Jewish Health, Denver CO

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Abstract

DESCRIPTION (Adapted from the Applicant's Abstract): The TNFalpha receptor CD120a, or p55, plays a critical role in the development of acute and chronic inflammatory diseases of the lung through its ability to signal the initiation of functions that include pro-inflammatory cytokine production and cell survival and death. The investigator has shown that CD120a is phosphorylated by the ERK. Once phosphorylated, receptor expression in plasma membrane microdomains (referred to as receptor rafts) is lost, and the receptor becomes associated with elements of the endoplasmic reticulum (ER-filaments). As a consequence of phosphorylation, cells become resistant to the induction of apoptotic cell death yet retain the ability to activate the transcription factor NF-kB. This may lead to the preservation of cells during the inflammatory response in the lung and in lung cancer, and may result in prolonged pro-inflammatory gene expression. The overall goal of this proposal is to investigate how the topographic distribution of the TNF receptor is regulated, and how this distribution regulates the pattern of receptor signaling. It is hypothesized: 1) that phosphorylation induces the trafficking of CD120a (p55) from receptor rafts to ER-filaments through the actions two novel CD120a (p55)-interacting proteins, TRIP197 and pTRIP82; and 2) that localization of the phosphorylated receptor to ER-filaments prevents apoptotic cell death by the assembly of a pro-survival signaling complex at the ER membrane. These hypotheses will be addressed by three specific aims: 1) to determine how de-phosphorylated CD120a (p55) is localized to receptor rafts and the specific role of TRIP197; 2) investigate the mechanism of translocation of phosphorylated CD120a (p55) to ER-filaments and the role of pTRIP82 in this event; and 3) investigate the mechanism by which cells are protected from apoptosis upon CD120a (p55) phosphorylation. The outcome of this work will have implications for understanding how topographical signaling by CD120a (p55) is regulated in inflammatory diseases and cancers of the lung.