Studies on the functions of the misshapen and E-Syt protein families in Wnt and FGF signalling during early xenopus development

Authors: Mikryukov, Alexander
Advisor: Moss, Tom
Abstract: The Wnt and FGF pathways are among the most critical inter-cellular signalling pathways controlling embryo development and the homeostasis of adult tissues. Although much is known about the signal transduction routes and proteins constituting these pathways, many questions concerning their regulation remain to be answered. The present work uses the Xenopus laevis model system to study the role of two kinases of the Misshapen family of MAP4K signalling kinases, xTNIK and xMINK, in the balance between canonical and non-canonical branches of Wnt signalling, and the role of a new endocytic adapter protein, E-Syt2, in regulation of FGF signalling by endocytosis. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical pathway regulating nuclear -catenin and a non-canonical pathway that activates the small GTPases Rac and RhoA, the JNK MAP-kinase and PKC. My work shows that xTNIK (Traf2 and Nck-interacting kinase) and xMINK (Misshapen/NIKs-related kinase) are essential and indeed integral components of both the canonical and non-canonical Wnt pathways. xTNIK and xMINK interact with each other and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology domain (CNH) fragments that are suppressive. The Kinase domain fragments of xTNIK mediate both canonical and non-canonical signalling, whereas those derived from xMINK mediate non-canonical signalling but strongly antagonize canonical signalling. This work suggests that tissue specific regulation of the proteolytic cleavage of xTNIK and xMINK controls the balance between canonical and non-canonical Wnt signalling. The synaptotagmin-related membrane protein E-Syt2 was found to be essential for an early phase of activated FGF receptor endocytosis that is necessary for functional ERK activation and mesoderm induction. E-Syt2 interacts selectively with the activated FGF receptor and with Adaptin-2, and is required upstream of Ras for ERK activation. Together these data identified E-Syt2 as an endocytic adapter for the Clathrin-dependent pathway.
Document Type: Thèse de doctorat
Issue Date: 2012
Open Access Date: 18 April 2018
Grantor: Université Laval
Collection:Thèses et mémoires

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