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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD066319-03
Application #
8657401
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Mukhopadhyay, Mahua
Project Start
2012-07-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
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
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
Collu, Giovanna M; Mlodzik, Marek (2015) Planar polarity: converting a morphogen gradient into cellular polarity. Curr Biol 25:R372-4
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
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
Mlodzik, Marek; Halder, Georg (2014) Walter J. Gehring (1939-2014). Dev Biol 395:1-3
Serysheva, Ekatherina; Mlodzik, Marek; Jenny, Andreas (2014) WNKs in Wnt/β-catenin signaling. Cell Cycle 13:173-4
Mlodzik, Marek; Halder, Georg (2014) Walter J Gehring (1939-2014). EMBO J 33:1615-6
Grumolato, Luca; Liu, Guizhong; Haremaki, Tomomi et al. (2013) β-Catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors. PLoS Genet 9:e1003603
Serysheva, Ekatherina; Berhane, Hebist; Grumolato, Luca et al. (2013) Wnk kinases are positive regulators of canonical Wnt/β-catenin signalling. EMBO Rep 14:718-25

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