Wnt canonical signaling plays critical roles in embryonic development and cell fate decisions and its constitutive activation has been directly implicated in human cancer. The noncanonical Wnt pathway, also importantly involved in development including planar cell polarity (PCP) and convergent extension, shares components with Wnt 2-catenin signaling including the Frizzled (Fz) receptors and Dishevelled (Dsh/Dvl). However, pathway signaling diverges downstream of Dsh/Dvl to activate strikingly different biochemical pathways and biological outcomes. This application investigates the molecular aspects of Wnt signaling specificity, taking advantage of complementary approaches and expertise involving both mammalian and Drosophila systems. Using a kinome shRNA screen we have identified two novel Dsh kinases, dWnk and dCDKL. Our preliminary studies indicate that these kinases specifically function in canonical and PCP pathways, respectively.
In Aim 1, we propose to further characterize Drosophila Wnk kinase in Wnt-pathway specific responses.
In Aim 2, we will investigate the role of mammalian Wnk kinases in Wnt canonical signaling and in Wnt-driven cancer cells.
In Aim 3, we will characterize the role of CDKL kinases in Wnt-signaling pathway responses. These investigations should elucidate novel components of Wnt pathways, lead to a better understanding of the evolutionary conservation and/or divergence of Wnt pathway specification, and possibly identify new therapeutic targets for Wnt activated human tumor cells. Our efforts are enhanced by close collaborative interactions among investigators, whose expertise and interrelated efforts strongly complement and help to inform these investigations.

Public Health Relevance

Wnt signaling pathways and associated regulatory factors have been implicated in many growth and patterning contexts and are linked to many diseases, ranging from ciliopathies and angiogenesis defects to cancer (e.g. several pathway components are tumor suppressors or proto-oncogenes). This proposal addresses critical aspects of Wnt pathway specification that are not yet elucidated, and the information acquired should significantly advance our understanding of Wnt signaling mechanisms in normal development and disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Mukhopadhyay, Mahua
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Vuong, Linh T; Iomini, Carlo; Balmer, Sophie et al. (2018) Kinesin-2 and IFT-A act as a complex promoting nuclear localization of ?-catenin during Wnt signalling. Nat Commun 9:5304
Vijayakumar, Sapna; Liu, Guizhong; Wen, Huei-Chi et al. (2017) Extracellular LDLR repeats modulate Wnt signaling activity by promoting LRP6 receptor endocytosis mediated by the Itch E3 ubiquitin ligase. Genes Cancer 8:613-627
Mlodzik, Marek (2016) The Dishevelled Protein Family: Still Rather a Mystery After Over 20 Years of Molecular Studies. Curr Top Dev Biol 117:75-91
Carvajal-Gonzalez, Jose Maria; Balmer, Sophie; Mendoza, Meg et al. (2015) The clathrin adaptor AP-1 complex and Arf1 regulate planar cell polarity in vivo. Nat Commun 6:6751
Collu, Giovanna M; Mlodzik, Marek (2015) Planar polarity: converting a morphogen gradient into cellular polarity. Curr Biol 25:R372-4
Galluzzi, L; Bravo-San Pedro, J M; Vitale, I et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22:58-73
Balmer, Sophie; Dussert, Aurore; Collu, Giovanna M et al. (2015) Components of Intraflagellar Transport Complex A Function Independently of the Cilium to Regulate Canonical Wnt Signaling in Drosophila. Dev Cell 34:705-18
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Serysheva, Ekatherina; Mlodzik, Marek; Jenny, Andreas (2014) WNKs in Wnt/?-catenin signaling. Cell Cycle 13:173-4
Mlodzik, Marek; Halder, Georg (2014) Walter J. Gehring (1939-2014). Dev Biol 395:1-3

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