Relaxin and its receptor RXFP1 in cell motility

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My research program has established relaxin (RLN2) and INSL3 and their cognate G protein coupled receptors, RXFP1 and RXFP2, as novel mediators of cell migration and extracellular matrix (ECM) degradation. These peptides induce the expression of powerful cathepsins, matrix-metalloproteinases MMP14, MMP2, and the MMP inhibitor TIMP2, and the Ca2+-binding protein S100A4 to facilitate ECM penetration and enhanced motility of thyroid cells. My recent discovery that RLN2 remodels the protein composition at the leading migrating edge of the protruding cell membrane, called pseudopodia, has opened new and exciting avenues in relaxin research. Proteins enriched by relaxin at the leading migrating edge can now be mapped to appreciate the impact of the RLN2-RXFP1 system in thyroid cells. Through targets like S100A4, RLN2 can activate the Wnt pathway to affect thyroid cell motility and I will explore the cross-talk between RXFP1 and Wnt signaling. Exposure of migrating cells to a changing micro-environment makes cells vulnerable to forms of programmed cell death (PCD). Employing novel 3D-nanoresolution imaging and other sophisticated tools available to me, I will explore if the anti-apoptotic actions of RXFP1 signaling we observed in-vivo can protect migrating cells against PCD. The successfully established new cre-lox transgenic (tg) mouse strain for the controlled tissue-specific activation of a constitutively active mutant RXFP1 will allow me now to generate double tg mice for thyroid-specific activation of RXFP1. These mice are then challenged by the induction of a hypothyroid and hyperthyroid stress and the effects of consistent RXFP1 signaling on thyroid endocrine system are evaluated. My unique program contributes new and unique data on the role of RLN2-RXFP1 in the thyroid. My previous data showed a significant functional overlap between the RLN2-RXFP1 and INSL3-RXFP2 in the thyroid. Thus, this proposal is likely to generate new and important data for both relaxin-like ligand-receptor systems in the thyroid.