The long term goal of this project is to uncover the regulatory networks that control the Hippo signaling pathway in response to mechanical stimuli, which could lead to better treatments for cancer, and improved stem cell therapies. The canonical Hippo pathway consists of two tumor suppressor kinases called MST1/2 and LATS1/2. MST1/2 activate LATS1/2, which in turn phosphorylates and inhibits the transcriptional co-activator and oncogene YAP, causing it to relocalize from the nucleus to the cytoplasm. When in the nucleus, the YAP promotes cell survival and proliferation. YAP nuclear localization is regulated by diverse mechanical stimuli such as substrate stiffness, cell detachment, cell crowding, and stretch to control density dependent inhibition of growth, tissue repair and stem cell proliferation and differentiation. Although these mechanical stimuli appear to affect Hippo signaling through effects on the F-actin cytoskeleton, the molecular mechanism for how F-actin perturbations are translated into changes in Hippo pathway signaling is largely unknown. Here we will identify how mechanical forces act on the core Hippo pathway.
In Specific Aim 1, we will determine how LATS1/2 activating kinases are regulated to turn on LATS1/2 in response to mechanical forces.
In Specific Aim 2, we will test various models for how angiomotin proteins act as sensors to regulate multiple aspects of Hippo signaling in response to mechanical stimuli that affect F-actin levels. We will determine in Specific Aim 3 how TRIP6 regulates LATS1/2 activity in response to cellular tension across sheets of cells. Overall these studies will reveal key molecular pathways controling Hippo signaling in response to mechanical forces. These studies will have an important impact on our understanding of tumor suppression and tissue regeneration and may lead to ways to manipulate these important processes.
The pathways studied in this proposal have important functions in cell proliferation, cancer, and stem cell homeostasis. This work will provide important insight into how these pathways work and and how their activities are be regulated, which could lead to better therapeutic approaches for cancer and tissue engineering.
| Dutta, Shubham; Mana-Capelli, Sebastian; Paramasivam, Murugan et al. (2018) TRIP6 inhibits Hippo signaling in response to tension at adherens junctions. EMBO Rep 19:337-350 |
| Mana-Capelli, Sebastian; McCollum, Dannel (2018) Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling. J Biol Chem 293:18230-18241 |
| Gupta, Sneha; Govindaraghavan, Meera; McCollum, Dannel (2014) Cross talk between NDR kinase pathways coordinates cytokinesis with cell separation in Schizosaccharomyces pombe. Eukaryot Cell 13:1104-12 |
| Li, Qi; Li, Shuangxi; Mana-Capelli, Sebastian et al. (2014) The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell 31:291-304 |
| Mana-Capelli, Sebastian; Paramasivam, Murugan; Dutta, Shubham et al. (2014) Angiomotins link F-actin architecture to Hippo pathway signaling. Mol Biol Cell 25:1676-85 |
| Gupta, Sneha; Mana-Capelli, Sebastian; McLean, Janel R et al. (2013) Identification of SIN pathway targets reveals mechanisms of crosstalk between NDR kinase pathways. Curr Biol 23:333-8 |
| Bajpai, Archana; Feoktistova, Anna; Chen, Jun-Song et al. (2013) Dynamics of SIN asymmetry establishment. PLoS Comput Biol 9:e1003147 |
| Cipak, Lubos; Gupta, Sneha; Rajovic, Iva et al. (2013) Crosstalk between casein kinase II and Ste20-related kinase Nak1. Cell Cycle 12:884-8 |
| Johnson, Alyssa E; McCollum, Dannel; Gould, Kathleen L (2012) Polar opposites: Fine-tuning cytokinesis through SIN asymmetry. Cytoskeleton (Hoboken) 69:686-99 |
| Mana-Capelli, Sebastian; McLean, Janel R; Chen, Chun-Ti et al. (2012) The kinesin-14 Klp2 is negatively regulated by the SIN for proper spindle elongation and telophase nuclear positioning. Mol Biol Cell 23:4592-600 |
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