Non-canonical Wnt signaling induces ubiquitination and degradation of Syndecan4.
Dynamic regulation of cell adhesion receptors is required for proper cell migration in embryogenesis, tissue repair, and cancer. Integrins and Syndecan4 (SDC4) are the main cell adhesion receptors involved in focal adhesion formation and are required for cell migration. SDC4 interacts biochemically and functionally with components of the Wnt pathway such as Frizzled7 and Dishevelled. Non-canonical Wnt signaling, particularly components of the planar cell polarity branch, controls cell adhesion and migration in embryogenesis and metastatic events. Here, we evaluate the effect of this pathway on SDC4. We have found that Wnt5a reduces cell surface levels and promotes ubiquitination and degradation of SDC4 in cell lines and dorsal mesodermal cells from Xenopus gastrulae. Gain- and loss-of-function experiments demonstrate that Dsh plays a key role in regulating SDC4 steady-state levels. Moreover, a SDC4 deletion construct that interacts inefficiently with Dsh is resistant to Wnt5a-induced degradation. Non-canonical Wnt signaling promotes monoubiquitination of the variable region of SDC4 cytoplasmic domain. Mutation of these specific residues abrogates ubiquitination and results in increased SDC4 steady-state levels. This is the first example of a cell surface protein ubiquitinated and degraded in a Wnt/Dsh-dependent manner.
Carvallo
Loreto
L
Center for Aging and Regeneration, Millenium Nucleus in Regenerative Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.
Muñoz
Rosana
R
Bustos
Francisco
F
Escobedo
Noelia
N
Carrasco
Héctor
H
Olivares
Gonzalo
G
Larraín
Juan
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000072261:Dishevelled Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D005775:Gastrula / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D053671:Syndecan-4; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C085096:Wnt5a protein, Xenopus; D029867:Xenopus Proteins