Sustained signaling for fibroblast migration

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Cell migration is a fundamental biological process that plays an important role in a wide range of biological and physiological processes. Its deregulation causes or contributes too many diseases, including pulmonary fibrosis. Based on the kinetics of fibroblast migration, we hypothesized that sustained signaling events, in addition to the acute ones, may be needed to support their slow-pace migration and subsequently identified one of the sustained signaling pathways as being critically important for LPA-induced fibroblast migration. In this pathway, LPA acts, through a G¿12-ARAF-ERK pathway, to transcriptionally upregulate the expression of an ubiquitin E3 ligase RFFL, which polyubiquitinates and destabilizes PRR5L, a specific inhibitor of PKC hydrophobic motif (HM) phosphorylation by mTORC2 (Mammalian target of rapamycin complex 2). The elimination of RFFL leads to sustained PKC HM phosphorylation and activation. This pathway is not only important for fibroblast migration in vitro, also appears to have a key role in pulmonary fibrosis development in a mouse model. In this study, we will investigate the signaling mechanisms downstream of the sustained PKC activation for the regulation of cell migration. We will also validate the importance of this sustained signaling pathway for cell migration in vivo and evaluate the therapeutic potential of a PKC inhibitor in a mouse model of idiopathic pulmonary fibrosis (IPF). IPF, in which LPA-induced fibroblast migration has an important role, is a terminal disease with no effective treatments.