PCatenin Independent Signaling

Historically, any signaling pathway activated by WNTs that did not lead to the stabilization of P-catenin was coined "noncanonical". Initially, that would only have included what is known in Drosophila as the PCP pathway and WNT-induced Ca2+ signaling. Recent development in the field of WNT signaling shows that P-catenin-independent signaling actually comprises a vast array of signaling pathways, indicating that the term "noncanonical" is a gross oversimplification [37]. Thus, it is more informative to distinguish the individual signaling branches by referring to the signaling components involved as identified by the original studies (see Table 5.2). In general P-catenin independent signaling regulates major reorganizations during embryonic development, such as tissue polarization and convergent extension movements [40]. Again, the Xenopus laevis embryo is a suitable model organism for the study of P-catenin-independent WNT signaling using, for example, Keller explants to investigate tissue elongation and constriction as a measure of convergent extension. In addition, polarized tissues exist not only in the fly but obviously also in vertebrate organisms, such as frog, fish, or mammals [37, 39]. The molecular signaling routes as summarized in Table 5.2 and in Semenov et al. [37] regulate crucial cellular processes, such as gene transcription, proliferation, differentiation, and cytoskeletal reorganization that rely on cell movements and polarization, to name but a few. Surprisingly, even though many 7 transmembrane spanning receptors have been shown to activate mitogen-activated protein kinases (MAPK) through diverse G protein-dependent and -independent mechanisms [49, 50] , only very few reports on WNT- induced regulation of extracellular signal-regulated kinases, a major proliferative pathway, have appeared [51].

P-catenin-independent signaling also appears as a regulator of P-catenin-dependent events, even though the precise mechanisms of this cross-talk are not clear yet [30, 52] - In the original report, WNT-5A was shown to decrease WNT- 3A signaling to P- catenin by an increase in the GSK3- dependent P -catenin degradation [ 52] - Recent evidence implicates a crucial role of the atypical receptor tyrosine kinase ROR2 for the WNT-5A-mediated inhibition of P-catenin signaling, which is of special relevance in cells that do not express ROR2 but respond to both WNT-3A and WNT-5A.

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