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Role of mechanosensors and Hippo pathway signaling in controlling cell fate decisions

The main interest of my lab is in understanding how the Hippo signaling pathway controls cellular responses to mechanical forces. The Hippo pathway is a protein kinase-mediated network that regulates cell proliferation, contact inhibition, apoptosis, stem cell maintenance and differentiation, and tissue regeneration. Misregulation of this pathway has deleterious effects on cells and organisms and can lead to cancer.  In the canonical pathway, MST1/2 kinases activate the LATS1/2 kinases, which in turn phosphorylate and inhibit the transcriptional co-activator YAP by causing its translocation from the nucleus to the cytoplasm. In the nucleus, YAP promotes cell survival and proliferation. YAP nuclear localization is regulated by diverse stimuli that affect the mechanical environment of the cell such as cell crowding, substrate stiffness, tension, and cell detachment. The ability to sense these types of changes to the mechanical environment is crucial for regulation of stem cell niches, wound healing, and contact inhibition of growth.

The Hippo pathway is known to monitor the mechanical environment both indirectly through the effects of various stimuli on the actin cytoskeleton, and more directly by sensing tension across tissues. My lab’s focus has been on determining how F-actin levels and tension at cell-cell junctions are sensed, and how these signals are transduced to control Hippo signaling. We identified the angiomotin proteins as candidate Hippo pathway sensors for F-actin levels. Our studies have also uncovered new Hippo pathway regulators at cell-cell junctions that may directly sense tension across tissues. Current research in the lab is focusing on understanding the molecular mechanisms underlying F-actin and tension sensing, and how signals from separate sensors are integrated to generate cellular responses to mechanical stimuli.

Rotation Projects

Rotation Projects

Analog sensitive LATS kinase:  The goal of this project is to use CRISPR based genome modification to make mutations in the endogenous LATS kinase that cause it to be inhibited by a synthetic ATP analog. This will allow LATS kinase activity to be turned on and off using the ATP analog. The analog sensitive cell line will be a valuable tool for studying Hippo pathway responses to various stimuli and will be used to test whether dephosphorylation of LATS substrates is an important regulatory mechanism. This project will also set the stage for future experiments to create mice that have analog sensitive versions of LATS. These mice will be used to test whether LATS inhibition is a viable treatment for regenerative therapies for the heart, gut, pancreas and other organs.

TRIP6 and Angiomotin interacting proteins: We know that cells monitor their mechanical environment by sensing F-actin levels and by measuring tension at cell-cell junctions. We have identified angiomotins as sensors for F-actin and the TRIP6 protein as part of a tension sensor at cell-cell junctions. However, to understand how these sensors work, we need know the network of proteins that they each interact with, and how those networks change in response to mechanical perturbations. To do this we will fuse each sensor to the promiscuous biotin ligase protein BirA, and express the fusion proteins in cells under various conditions. The biotin ligase will label proteins in close proximity with biotin. Labeled proteins will be purified and analyzed by mass spectrometry, and the spectrum of interacting partners under different conditions will be compared.

One or more keywords matched the following items that are connected to McCollum, Dannel
Item TypeName
Academic Article Role of polo kinase and Mid1p in determining the site of cell division in fission yeast.
Academic Article Identification of cold-sensitive mutations in the Schizosaccharomyces pombe actin locus.
Academic Article Sid2p, a spindle pole body kinase that regulates the onset of cytokinesis.
Academic Article The role of the sid1p kinase and cdc14p in regulating the onset of cytokinesis in fission yeast.
Academic Article Mob1p interacts with the Sid2p kinase and is required for cytokinesis in fission yeast.
Academic Article Timing is everything: regulation of mitotic exit and cytokinesis by the MEN and SIN.
Academic Article Fission yeast Clp1p phosphatase regulates G2/M transition and coordination of cytokinesis with cell cycle progression.
Academic Article Cytokinesis: myosin spots the ring.
Academic Article Dma1 prevents mitotic exit and cytokinesis by inhibiting the septation initiation network (SIN).
Academic Article Scw1p antagonizes the septation initiation network to regulate septum formation and cell separation in the fission yeast Schizosaccharomyces pombe.
Academic Article Initiation of cytokinesis is controlled through multiple modes of regulation of the Sid2p-Mob1p kinase complex.
Academic Article A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast.
Academic Article Centrosomes in cellular regulation.
Academic Article Cytokinesis: breaking the ties that bind.
Academic Article Molecular biology. The mad ways of meiosis.
Academic Article The nucleolar Net1/Cfi1-related protein Dnt1 antagonizes the septation initiation network in fission yeast.
Academic Article Interaction between the noncatalytic region of Sid1p kinase and Cdc14p is required for full catalytic activity and localization of Sid1p.
Academic Article The meiosis-specific Sid2p-related protein Slk1p regulates forespore membrane assembly in fission yeast.
Academic Article The SIN kinase Sid2 regulates cytoplasmic retention of the S. pombe Cdc14-like phosphatase Clp1.
Academic Article Proper timing of cytokinesis is regulated by Schizosaccharomyces pombe Etd1.
Academic Article The multiprotein exocyst complex is essential for cell separation in Schizosaccharomyces pombe.
Academic Article Cytokinesis: ER keeps Mid1 in the middle.
Academic Article Prevention of merotelic chromosome attachments by the monopolin complex.
Academic Article Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor.
Academic Article Dnt1 acts as a mitotic inhibitor of the spindle checkpoint protein dma1 in fission yeast.
Academic Article The kinesin-14 Klp2 is negatively regulated by the SIN for proper spindle elongation and telophase nuclear positioning.
Academic Article Mob2p interacts with the protein kinase Orb6p to promote coordination of cell polarity with cell cycle progression.
Academic Article Dynamics of SIN asymmetry establishment.
Academic Article The Clp1p/Flp1p phosphatase ensures completion of cytokinesis in response to minor perturbation of the cell division machinery in Schizosaccharomyces pombe.
Academic Article The S. pombe Cdc14-like phosphatase Clp1p regulates chromosome biorientation and interacts with Aurora kinase.
Academic Article Cytokinesis: the central spindle takes center stage.
Academic Article Distinct nuclear and cytoplasmic functions of the S. pombe Cdc14-like phosphatase Clp1p/Flp1p and a role for nuclear shuttling in its regulation.
Academic Article A role for the septation initiation network in septum assembly revealed by genetic analysis of sid2-250 suppressors.
Academic Article S. pombe FEAR protein orthologs are not required for release of Clp1/Flp1 phosphatase from the nucleolus during mitosis.
Academic Article Phosphorylation state defines discrete roles for monopolin in chromosome attachment and spindle elongation.
Academic Article The mitosis-to-interphase transition is coordinated by cross talk between the SIN and MOR pathways in Schizosaccharomyces pombe.
Academic Article A role for metaphase spindle elongation forces in correction of merotelic kinetochore attachments.
Academic Article The SET domain protein, Set3p, promotes the reliable execution of cytokinesis in Schizosaccharomyces pombe.
Academic Article A highly efficient multifunctional tandem affinity purification approach applicable to diverse organisms.
Academic Article Polar opposites: Fine-tuning cytokinesis through SIN asymmetry.
Academic Article Identification of SIN pathway targets reveals mechanisms of crosstalk between NDR kinase pathways.
Academic Article Crosstalk between casein kinase II and Ste20-related kinase Nak1.
Concept Membrane Proteins
Concept DNA-Binding Proteins
Concept 14-3-3 Proteins
Concept Qa-SNARE Proteins
Concept rho GTP-Binding Proteins
Concept Carrier Proteins
Concept Chromosomal Proteins, Non-Histone
Concept Cell Cycle Proteins
Concept Luminescent Proteins
Concept Nuclear Proteins
Concept Recombinant Proteins
Concept Intracellular Signaling Peptides and Proteins
Concept Intercellular Signaling Peptides and Proteins
Concept Schizosaccharomyces pombe Proteins
Concept Proteins
Concept Microtubule-Associated Proteins
Concept F-Box Proteins
Concept Cytoskeletal Proteins
Concept Adaptor Proteins, Signal Transducing
Concept Green Fluorescent Proteins
Concept Bacterial Proteins
Concept Recombinant Fusion Proteins
Concept Calcium-Binding Proteins
Concept SNARE Proteins
Concept Fungal Proteins
Concept Saccharomyces cerevisiae Proteins
Concept Neoplasm Proteins
Concept Caenorhabditis elegans Proteins
Concept Drosophila Proteins
Concept Microfilament Proteins
Concept Tumor Suppressor Proteins
Concept RNA-Binding Proteins
Academic Article Angiomotins link F-actin architecture to Hippo pathway signaling.
Academic Article An efficient fluorescent protein-based multifunctional affinity purification approach in mammalian cells.
Academic Article Cross talk between NDR kinase pathways coordinates cytokinesis with cell separation in Schizosaccharomyces pombe.
Academic Article The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila.
Academic Article TRIP6 inhibits Hippo signaling in response to tension at adherens junctions.
Academic Article Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling.
Academic Article Control of cellular responses to mechanical cues through YAP/TAZ regulation.
Concept LIM Domain Proteins
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