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    Dannel McCollum PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street
    Worcester MA 01605
    Phone508-856-8767
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Cell Dynamics

        Overview 
        Narrative

        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.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. McCollum for additional details.

        Bibliographic 
        selected publications
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        1. Li Q, Li S, Mana-Capelli S, Roth Flach RJ, Danai LV, Amcheslavsky A, Nie Y, Kaneko S, Yao X, Chen X, Cotton JL, Mao J, McCollum D, Jiang J, Czech MP, Xu L, Ip YT. The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell. 2014 Nov 10; 31(3):291-304.
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        2. Gupta S, Govindaraghavan M, McCollum D. Cross talk between NDR kinase pathways coordinates cytokinesis with cell separation in Schizosaccharomyces pombe. Eukaryot Cell. 2014 Aug; 13(8):1104-12.
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        3. Mana-Capelli S, Paramasivam M, Dutta S, McCollum D. Angiomotins link F-actin architecture to Hippo pathway signaling. Mol Biol Cell. 2014 May; 25(10):1676-85.
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        4. Ma H, McLean JR, Gould KL, McCollum D. An efficient fluorescent protein-based multifunctional affinity purification approach in mammalian cells. Methods Mol Biol. 2014; 1177:175-91.
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        5. Bajpai A, Feoktistova A, Chen JS, McCollum D, Sato M, Carazo-Salas RE, Gould KL, Csikász-Nagy A. Dynamics of SIN asymmetry establishment. PLoS Comput Biol. 2013; 9(7):e1003147.
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        6. Cipak L, Gupta S, Rajovic I, Jin QW, Anrather D, Ammerer G, McCollum D, Gregan J. Crosstalk between casein kinase II and Ste20-related kinase Nak1. Cell Cycle. 2013 Mar 15; 12(6):884-8.
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        7. Gupta S, Mana-Capelli S, McLean JR, Chen CT, Ray S, Gould KL, McCollum D. Identification of SIN pathway targets reveals mechanisms of crosstalk between NDR kinase pathways. Curr Biol. 2013 Feb 18; 23(4):333-8.
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        8. McCollum D. Monopolin. Curr Biol. 2012 Nov 20; 22(22):R937-8.
          View in: PubMed
        9. Mana-Capelli S, McLean JR, Chen CT, Gould KL, McCollum D. The kinesin-14 Klp2 is negatively regulated by the SIN for proper spindle elongation and telophase nuclear positioning. Mol Biol Cell. 2012 Dec; 23(23):4592-600.
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        10. Wang Y, Li WZ, Johnson AE, Luo ZQ, Sun XL, Feoktistova A, McDonald WH, McLeod I, Yates JR, Gould KL, McCollum D, Jin QW. Dnt1 acts as a mitotic inhibitor of the spindle checkpoint protein dma1 in fission yeast. Mol Biol Cell. 2012 Sep; 23(17):3348-56.
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        11. Johnson AE, McCollum D, Gould KL. Polar opposites: Fine-tuning cytokinesis through SIN asymmetry. Cytoskeleton (Hoboken). 2012 Oct; 69(10):686-99.
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        12. Ma H, McLean JR, Chao LF, Mana-Capelli S, Paramasivam M, Hagstrom KA, Gould KL, McCollum D. A highly efficient multifunctional tandem affinity purification approach applicable to diverse organisms. Mol Cell Proteomics. 2012 Aug; 11(8):501-11.
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        13. Rentas S, Saberianfar R, Grewal C, Kanippayoor R, Mishra M, McCollum D, Karagiannis J. The SET domain protein, Set3p, promotes the reliable execution of cytokinesis in Schizosaccharomyces pombe. PLoS One. 2012; 7(2):e31224.
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        14. Choi SH, McCollum D. A role for metaphase spindle elongation forces in correction of merotelic kinetochore attachments. Curr Biol. 2012 Feb 7; 22(3):225-30.
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        15. Gupta S, McCollum D. Crosstalk between NDR kinase pathways coordinates cell cycle dependent actin rearrangements. Cell Div. 2011; 6:19.
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        16. Paramasivam M, Sarkeshik A, Yates JR, Fernandes MJ, McCollum D. Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor. Mol Biol Cell. 2011 Oct; 22(19):3725-33.
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        17. McCollum D. Prevention of merotelic chromosome attachments by the monopolin complex. Cell Cycle. 2010 Nov 1; 9(21):4258.
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        18. Ray S, Kume K, Gupta S, Ge W, Balasubramanian M, Hirata D, McCollum D. The mitosis-to-interphase transition is coordinated by cross talk between the SIN and MOR pathways in Schizosaccharomyces pombe. J Cell Biol. 2010 Sep 6; 190(5):793-805.
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        19. McCollum D. Cytokinesis: ER keeps Mid1 in the middle. Curr Biol. 2010 Jun 8; 20(11):R484-6.
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        20. García-Cortés JC, McCollum D. Proper timing of cytokinesis is regulated by Schizosaccharomyces pombe Etd1. J Cell Biol. 2009 Sep 7; 186(5):739-53.
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        21. Choi SH, Péli-Gulli MP, Mcleod I, Sarkeshik A, Yates JR, Simanis V, McCollum D. Phosphorylation state defines discrete roles for monopolin in chromosome attachment and spindle elongation. Curr Biol. 2009 Jun 23; 19(12):985-95.
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        22. Chen CT, Feoktistova A, Chen JS, Shim YS, Clifford DM, Gould KL, McCollum D. The SIN kinase Sid2 regulates cytoplasmic retention of the S. pombe Cdc14-like phosphatase Clp1. Curr Biol. 2008 Oct 28; 18(20):1594-9.
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        23. Yan H, Ge W, Chew TG, Chow JY, McCollum D, Neiman AM, Balasubramanian MK. The meiosis-specific Sid2p-related protein Slk1p regulates forespore membrane assembly in fission yeast. Mol Biol Cell. 2008 Sep; 19(9):3676-90.
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        24. Clifford DM, Chen CT, Roberts RH, Feoktistova A, Wolfe BA, Chen JS, McCollum D, Gould KL. The role of Cdc14 phosphatases in the control of cell division. Biochem Soc Trans. 2008 Jun; 36(Pt 3):436-8.
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        25. Jin QW, Ray S, Choi SH, McCollum D. The nucleolar Net1/Cfi1-related protein Dnt1 antagonizes the septation initiation network in fission yeast. Mol Biol Cell. 2007 Aug; 18(8):2924-34.
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        26. Chen CT, Peli-Gulli MP, Simanis V, McCollum D. S. pombe FEAR protein orthologs are not required for release of Clp1/Flp1 phosphatase from the nucleolus during mitosis. J Cell Sci. 2006 Nov 1; 119(Pt 21):4462-6.
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        27. Jin QW, Zhou M, Bimbo A, Balasubramanian MK, McCollum D. A role for the septation initiation network in septum assembly revealed by genetic analysis of sid2-250 suppressors. Genetics. 2006 Apr; 172(4):2101-12.
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        28. McCollum D. Cytokinesis: breaking the ties that bind. Curr Biol. 2005 Dec 20; 15(24):R998-1000.
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        29. Trautmann S, McCollum D. Distinct nuclear and cytoplasmic functions of the S. pombe Cdc14-like phosphatase Clp1p/Flp1p and a role for nuclear shuttling in its regulation. Curr Biol. 2005 Aug 9; 15(15):1384-9.
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        30. Doxsey S, McCollum D, Theurkauf W. Centrosomes in cellular regulation. Annu Rev Cell Dev Biol. 2005; 21:411-34.
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        31. McCollum D. Cytokinesis: the central spindle takes center stage. Curr Biol. 2004 Nov 23; 14(22):R953-5.
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        32. Trautmann S, Rajagopalan S, McCollum D. The S. pombe Cdc14-like phosphatase Clp1p regulates chromosome biorientation and interacts with Aurora kinase. Dev Cell. 2004 Nov; 7(5):755-62.
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        33. Mishra M, Karagiannis J, Trautmann S, Wang H, McCollum D, Balasubramanian MK. The Clp1p/Flp1p phosphatase ensures completion of cytokinesis in response to minor perturbation of the cell division machinery in Schizosaccharomyces pombe. J Cell Sci. 2004 Aug 1; 117(Pt 17):3897-910.
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        34. Mitra P, Zhang Y, Rameh LE, Ivshina MP, McCollum D, Nunnari JJ, Hendricks GM, Kerr ML, Field SJ, Cantley LC, Ross AH. A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast. J Cell Biol. 2004 Jul 19; 166(2):205-11.
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        35. Hou MC, Guertin DA, McCollum D. Initiation of cytokinesis is controlled through multiple modes of regulation of the Sid2p-Mob1p kinase complex. Mol Cell Biol. 2004 Apr; 24(8):3262-76.
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        36. Jin QW, McCollum D. Scw1p antagonizes the septation initiation network to regulate septum formation and cell separation in the fission yeast Schizosaccharomyces pombe. Eukaryot Cell. 2003 Jun; 2(3):510-20.
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        37. Hou MC, Wiley DJ, Verde F, McCollum D. Mob2p interacts with the protein kinase Orb6p to promote coordination of cell polarity with cell cycle progression. J Cell Sci. 2003 Jan 1; 116(Pt 1):125-35.
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        38. Guertin DA, Venkatram S, Gould KL, McCollum D. Dma1 prevents mitotic exit and cytokinesis by inhibiting the septation initiation network (SIN). Dev Cell. 2002 Dec; 3(6):779-90.
          View in: PubMed
        39. Trautmann S, McCollum D. Cell cycle: new functions for Cdc14 family phosphatases. Curr Biol. 2002 Oct 29; 12(21):R733-5.
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        40. McCollum D. First things first: spindle orientation and mitotic progression. Nat Cell Biol. 2002 Oct; 4(10):E225-6.
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        41. Guertin DA, Trautmann S, McCollum D. Cytokinesis in eukaryotes. Microbiol Mol Biol Rev. 2002 Jun; 66(2):155-78.
          View in: PubMed
        42. Hou MC, McCollum D. Cytokinesis: myosin spots the ring. Curr Biol. 2002 Apr 30; 12(9):R334-6.
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        43. Wang H, Tang X, Liu J, Trautmann S, Balasundaram D, McCollum D, Balasubramanian MK. The multiprotein exocyst complex is essential for cell separation in Schizosaccharomyces pombe. Mol Biol Cell. 2002 Feb; 13(2):515-29.
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        44. Trautmann S, Wolfe BA, Jorgensen P, Tyers M, Gould KL, McCollum D. Fission yeast Clp1p phosphatase regulates G2/M transition and coordination of cytokinesis with cell cycle progression. Curr Biol. 2001 Jun 26; 11(12):931-40.
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        45. Guertin DA, McCollum D. Interaction between the noncatalytic region of Sid1p kinase and Cdc14p is required for full catalytic activity and localization of Sid1p. J Biol Chem. 2001 Jul 27; 276(30):28185-9.
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        46. McCollum D, Gould KL. Timing is everything: regulation of mitotic exit and cytokinesis by the MEN and SIN. Trends Cell Biol. 2001 Feb; 11(2):89-95.
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        47. Sluder G, McCollum D. Molecular biology. The mad ways of meiosis. Science. 2000 Jul 14; 289(5477):254-5.
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        48. Hou MC, Salek J, McCollum D. Mob1p interacts with the Sid2p kinase and is required for cytokinesis in fission yeast. Curr Biol. 2000 May 18; 10(10):619-22.
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        49. Guertin DA, Chang L, Irshad F, Gould KL, McCollum D. The role of the sid1p kinase and cdc14p in regulating the onset of cytokinesis in fission yeast. EMBO J. 2000 Apr 17; 19(8):1803-15.
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        50. Sparks CA, Morphew M, McCollum D. Sid2p, a spindle pole body kinase that regulates the onset of cytokinesis. J Cell Biol. 1999 Aug 23; 146(4):777-90.
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        51. McCollum D, Balasubramanian M, Gould K. Identification of cold-sensitive mutations in the Schizosaccharomyces pombe actin locus. FEBS Lett. 1999 May 28; 451(3):321-6.
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        52. Bähler J, Steever AB, Wheatley S, Wang Yl, Pringle JR, Gould KL, McCollum D. Role of polo kinase and Mid1p in determining the site of cell division in fission yeast. J Cell Biol. 1998 Dec 14; 143(6):1603-16.
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