"Molecular mechanisms of Repulsive Guidance Molecules (RGMs) in BMP and Neogenin signalling – from cell migration to morphogen regulation"
|Dates:||10 March 2015|
|Times:||13:00 - 14:00|
|What is it:||Seminar|
|Organiser:||Faculty of Life Sciences|
|Who is it for:||University staff, Current University students|
Part of the Tissue Systems seminar series.
Repulsive Guidance Molecules (RGMs) were initially identified and named for their ability to repel neurons grown from chicken retinas. We now know that the three RGM family members control a large and diverse range of cellular functions, from immune cell regulation (RGMA), to cell motility (RGMB), and iron homeostasis (RGMC). Due to their numerous roles, abnormal RGM function or expression has been linked to various diseases including multiple sclerosis, cancer and blood diseases. RGMs are tethered to the outside of the plasma membrane where they function to mediate crucial cell-to-cell communication in the extracellular matrix. RGMs can signal by binding directly to the cell surface guidance receptor Neogenin (NEO1) a member of the immunoglobulin super family and an paralogue of the Netrin receptor DCC (Deleted in Colorectal Cancer), but also act as activators of Bone Morphogenetic Protein (BMP) signalling, a fundamental morphogen pathway in development.
Despite numerous genetic and functional studies, the molecular mechanisms underlying extracellular RGM reception and signal transduction still remain poorly understood. Here, I present you structural and functional data on RGM complexes with NEO1, suggesting a mechanism by which two RGM molecules act as a molecular staple, bringing together the juxtamembrane regions of two NEO1 receptors, thus resulting in downstream signalling and actin cytoskeleton rearrangements important for the RGM-mediated function in processes of cell migration. Furthermore, our molecular analysis on RGM complexes with the BMP ligand BMP2, together with biophysical and cellular experiments, suggest a mechanism for RGM-mediated activation of BMP signalling that is dependent on pH and cellular localisation, and offers a molecular rationale for RGM mutations causing the blood disease juvenile hemochromatosis (JHH). Finally, the crystal structure of a ternary BMP-NEO1-RGM complex, supported by solution scattering data and quantitative super-resolution microscopic clustering analysis, provides direct evidence of a physical link between the NEO1 and BMP pathways bridged by RGMs, thus putting forward an important new mechanism for cellular signalling.
Organisation: University of Oxford
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