Role of Misshappen (NIK/Msn) kinases and Extended-Synaptotagmins (E-Syts) in Wnt and FGF intracellular signaling pathways.

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Signalling between cells is fundamental to determining the metazoan body plan and in controlling growth and differentiation. Hence, a large number of families of signalling molecules and their cognate receptors have evolved to enable the complexities of early development, organogensis and homeostasis. Several of these families are of importance during early development, in particular the Wingless (Wnt) and Fibroblast Growth Factors (FGFs) families. These play separate, but interrelated, roles during development and act through distinct as well as shared transduction pathways. We have identified novel elements of the FGF and Wnt signalling pathways that provide potential windows into important aspects of signalling and inter-pathway crosstalk. We propose mechanistic studies that will provide new insight into the complex network of intracellular signalling.******We were first to identify a role for the Extended Synaptotagmin 2 (ESyt2) in FGF signalling. The ESyts are a multi-C2-domain phospholipid-binding membrane protein, that function as endocytic adapters for the FGF Receptors (FGFRs). ESyt2 regulates the MAP-kinase pathway by mediating FGFR endocytosis, and plays probably related roles in endoplasmic reticulum - plasma membrane (ER-PM) junctioning, Store Operated Calcium Entry (SOCE)/Ca2+-signaling, and transport of phospholipids to the PM. To understand their physiological roles, we have generated ESyt1/2/3-null mice, established ESyt-null cell lines and shown them to have defects in Ca2+ signalling, and have begun genetic studies of the unique ESyt ortholog in Drosophila. We propose to use these tools to determine the in vitro and in vivo functions of the ESyts and how they impinge on phospholipid metabolism, and affect FGF and potentially Wnt signal transduction.******Wnt signalling has been established as a key player in developmental patterning. However, despite considerable scientific effort, our understanding of crosstalk between the canonical beta-catenin, non-canonical Planar Cell Polarity and Ca2+ signalling pathways remains rudimentary. We recently discovered that the Xenopus Misshapen (Msn) homologs TNIK and MINK signalling kinases form integral components of both the canonical and non-canonical Wnt pathways. Our data strongly suggest the balance between the canonical and non-canonical pathways is controlled by proteolysis of TNIK and MINK, which determines both their kinase activities and subcellular locations. We have shown that this cleavage is conserved, since the unique Drosophila Msn is also cleaved during development. We propose a series of genetic, cell and molecular studies to determine the developmental and physiological significance of Msn cleavage, and hence to better understand the complex control of Wnt signalling.