The long term goals of this project are to understand how Ndr kinase pathways are regulated and carry out their important roles in cell cycle progression, cytoskeletal organization, tumor suppression, and stem cell differentiation. Major rearrangements of the cytoskeleton are required for the transition between interphase and mitosis as well as undifferentiated to differentiated states. Failure to properly regulate cytoskeletal rearrangements can have profound effects including genomic instability, stem cell differentiation defects, cancer, and metastasis. Eukaryotic cells possess two conserved Ndr kinase pathways, called the SIN and MOR in fission yeast (S. pombe) or the Hippo/Lats and Ndr1/2 pathways in mammals. The two pathways are functionally distinct: the Hippo/Lats and SIN pathways play roles in cytokinesis and mitotic exit whereas the Ndr1/2 and MOR pathways function in cell polarity. In metazoans they have acquired additional functions in contact inhibition of growth, tumor suppression, and stem cell differentiation (Hippo/Lats), or growth promotion, chromosome congression and centrosome duplication (Ndr1/2). Despite their crucial functions in cell division, cell polarity, and development, few targets of these pathways are known.
In Specific Aim 1, we will determine how signaling is coordinated between the MOR, Cdk1, and the SIN and whether this regulation is conserved in human cells. We will determine in Specific Aim 2 how newly identified targets of the SIN are regulated in late mitosis to promote cytokinesis, microtubule organization, and spindle checkpoint inactivation.
In Specific Aim 3, we will identify substrates of the Hippo/Lats pathway and test hypotheses for how the pathway is activated in response to increased cell density to stop cell cycle progression. Overall these studies will show how the SIN promotes late mitotic events through substrate phosphorylation and crosstalk with the MOR pathway. Our studies on Lats2 targets and activation will have important implications for the processes of tumor suppression and tissue regeneration.

Public Health Relevance

The pathways studied in this proposal have important functions in cell proliferation, cancer, and stem cell differentiation. This work will provide important insight into how these pathways work and how their activities are be regulated, which should lead to therapeutic approaches for cancer and tissue engineering. )

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058406-15
Application #
8462988
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Gindhart, Joseph G
Project Start
1998-03-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
15
Fiscal Year
2013
Total Cost
$398,388
Indirect Cost
$158,876
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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; Govindaraghavan, Meera; McCollum, Dannel (2014) Cross talk between NDR kinase pathways coordinates cytokinesis with cell separation in Schizosaccharomyces pombe. Eukaryot Cell 13:1104-12
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
Cipak, Lubos; Gupta, Sneha; Rajovic, Iva et al. (2013) Crosstalk between casein kinase II and Ste20-related kinase Nak1. Cell Cycle 12:884-8
Paramasivam, Murugan; Sarkeshik, Ali; Yates 3rd, John R et al. (2011) Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor. Mol Biol Cell 22:3725-33
Ray, Samriddha; Kume, Kazunori; Gupta, Sneha et al. (2010) The mitosis-to-interphase transition is coordinated by cross talk between the SIN and MOR pathways in Schizosaccharomyces pombe. J Cell Biol 190:793-805
Garcia-Cortes, Juan Carlos; McCollum, Dannel (2009) Proper timing of cytokinesis is regulated by Schizosaccharomyces pombe Etd1. J Cell Biol 186:739-53
Yan, Hongyan; Ge, Wanzhong; Chew, Ting Gang et al. (2008) The meiosis-specific Sid2p-related protein Slk1p regulates forespore membrane assembly in fission yeast. Mol Biol Cell 19:3676-90
Jin, Quan-Wen; Ray, Samriddha; Choi, Sung Hugh et al. (2007) The nucleolar Net1/Cfi1-related protein Dnt1 antagonizes the septation initiation network in fission yeast. Mol Biol Cell 18:2924-34
Jin, Quan-Wen; Zhou, Mian; Bimbo, Andrea et al. (2006) A role for the septation initiation network in septum assembly revealed by genetic analysis of sid2-250 suppressors. Genetics 172:2101-12

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