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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 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 Fission yeast Clp1p phosphatase regulates G2/M transition and coordination of cytokinesis with cell cycle progression.
Academic Article Cytokinesis in eukaryotes.
Academic Article Dma1 prevents mitotic exit and cytokinesis by inhibiting the septation initiation network (SIN).
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 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 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 The S. pombe Cdc14-like phosphatase Clp1p regulates chromosome biorientation and interacts with Aurora kinase.
Academic Article Phosphorylation state defines discrete roles for monopolin in chromosome attachment and spindle elongation.
Academic Article Crosstalk between NDR kinase pathways coordinates cell cycle dependent actin rearrangements.
Academic Article A role for metaphase spindle elongation forces in correction of merotelic kinetochore attachments.
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 Protein-Tyrosine Kinases
Concept Cyclin-Dependent Kinases
Concept Mitogen-Activated Protein Kinase Kinases
Concept Cyclin-Dependent Kinase Inhibitor p21
Concept CDC2 Protein Kinase
Concept Protein Kinases
Concept MAP Kinase Kinase Kinases
Concept Phosphotransferases (Alcohol Group Acceptor)
Concept Phosphatidylinositol 3-Kinases
Concept Casein Kinase II
Academic Article Angiomotins link F-actin architecture to Hippo pathway signaling.
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.
Concept Aurora Kinases
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