Brooke M. McCartney
600D Mellon Institute
Department of Biological Sciences
Carnegie Mellon University
4400 Fifth Avenue
Pittsburgh, PA 15213
Ph.D., Duke University
Postdoctoral Appointment, University of North Carolina at Chapel Hill
Dynamic rearrangements of the actin and microtubule cytoskeletons, and changes in cell shape, are hallmarks of morphogenesis. Despite an abundance of examples of such events during development, we understand remarkably little about the molecular mechanisms that underlie these processes, both at the level of the proteins that directly influence the cytoskeleton and at the level of the signals that activate those players. In order to identify and dissect these molecular mechanisms, we have taken a reverse genetic approach focusing our studies on understanding the cytoskeletal roles of the protein Adenomatous polyposis coli (APC). APC was first identified in humans as the colon cancer tumor suppressor; loss of heterozygosity of APC is now known to be the initiating event in the majority of both familial and sporadic cases of colon carcinogenesis. Since its discovery in 1991, a tremendous research effort has been made to determine why loss of heterozygosity of APC initiates polyposis in the colon. The results of this effort have revealed that APC is a complex, multifunctional protein that influences both Wnt signal transduction and cytoskeletal organization. Given its role in both signaling and cytoskeletal organization, and its relevance to cancer development, we chose APC as the nexus of our studies of cytoskeletal and tissue level morphogenesis using the Drosophila model system.
APC is a negative regulator of Wnt signaling transduction. In the simplest models, APC acts as part of a complex of proteins referred to as the destruction complex that binds to cytoplasmic ß-catenin, a key effector of Wnt signaling, and targets it for proteosomal degradation in the absence of Wnt signals.
Binding of the Wnt ligand to its receptor results in the deactivation of the destruction complex and the consequent increase in cytoplasmic ß-catenin. ß-catenin can then enter the nucleus and activate Wnt target genes together with a host of other transcription factors. While this simple model of APC function as a negative regulator is well appreciated, the precise mechanisms by which APC functions have remained elusive. Surprisingly, APC proteins are also implicated in cytoskeletal functions that are thought to be independent of its role in signaling. APC proteins have been reported to facilitate microtubule-cortical contacts and microtubule-kinetochore contacts, and enhance microtubule stability. Further, APC proteins influence actin organization, although this is less well understood. Thus, while there exists a substantial literature describing APC’s associations with the cytoskeleton, there remain significant gaps in our understanding of how the APC proteins function and what the implications are for dynamic cytoskeletal rearrangements in cells in tissue in whole organisms.
Our studies are focused on:
- A structure-function analysis of Drosophila APC2 to determine the requirements for APC2’s localization to the actin cortex.
- Dissecting the role of Drosophila APC2 in actin organization in the syncytial blastoderm stage embryo.
- Assessing the consequences of complete loss of both Drosophila APC1 and APC2 on epithelial morphogenesis in the wing imaginal disc.
For a more detailed description of our research interests, please visit our website: www.bio.cmu.edu/labs/mccartney/index.html
Kunttas-Tatli E, Roberts DM, McCartney BM. Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex. Mol Biol Cell. 2014 Sep 10.
Komori H, Xiao Q, McCartney BM, Lee CY. Brain tumor specifies intermediate progenitor cell identity by attenuating β-catenin/Armadillo activity. Development. 2014 Jan;141(1):51-62
Jaiswal R, Stepanik V, Rankova A, Molinar O, Goode BL, McCartney BM. Drosophila homologues of adenomatous polyposis coli (APC) and the formin diaphanous collaborate by a conserved mechanism to stimulate actin filament assembly. J Biol Chem. 2013 May 10;288(19):13897-905.
Kunttas-Tatli E, Zhou MN, Zimmerman S, Molinar O, Zhouzheng F, Carter K, Kapur M, Cheatle A†, Decal R, McCartney BM*. Destruction complex function in the Wnt signaling pathway of Drosophila requires multiple interactions between Adenomatous polyposis coli 2 and Armadillo. Genetics. 2012 Mar;190(3):1059-75. Epub 2011 Dec 14.
Stadler AL, Delos Santos JO, Stensrud ES, Dembska A, Silva GL, Liu S, Shank NI, Kunttas-Tatli E, Sobers CJ, Gramlich PM, Carell T, Peteanu LA, McCartney BM, Armitage BA. Fluorescent DNA Nanotags Featuring Covalently Attached Intercalating Dyes: Synthesis, Antibody Conjugation and Intracellular Imaging. Bioconjugate Chemistry 22(8):1491-1502, 2011 Aug 17.
Zhou M-N, Kunttas-Tatli E, Zimmerman S, Zhouzheng F, McCartney BM. Cortical localization of APC2 plays a role in actin organization but not in Wnt signaling in Drosophila. Journal of Cell Science, 124(Pt 9):1589-600, 2011 May 1.
Zimmerman SG, Thorpe LM, Medrano VR, Mallozzi CA, McCartney BM. Apical constriction and invagination downstream of the canonical Wnt signaling pathway requires Rho1 and Myosin II. Developmental Biology 340:54-66, 2010.
Webb RL, Rozov O, Watkins S, McCartney BM. Using Total Internal Reflection Fluorescence (TIRF) microscopy to visualize cortical actin and microtubules in the Drosophila syncytial embryo. Developmental Dynamics; 238:2622-2632, 2009.
Webb RL, Zhou MN, McCartney BM. A novel role for an APC2-Diaphanous complex in regulating actin organization in Drosophila. Development; 136(8):1283-93, 2009 Apr. Epub 2009 Mar 11.
McCartney BM, Näthke IS. Cell regulation by the Apc protein Apc as master regulator of epithelia. Curr Opin Cell Biol 2008 Apr; 20(2):186-93, Epub 2008 Mar 24.
McCartney BM, Price MH, Webb RL, Hayden MA, Holot LM, Zhou M, Bejsovec A, Peifer M. Testing hypotheses for the functions of APC family proteins using null and truncation alleles in Drosophila. Development; 133(12):2407-18, 2006 Jun.
Akong K, McCartney BM and Peifer M. Drosophila APC2 and APC1 have overlapping roles in the larval brain despite their distinct intracellular localizations. Developmental Biology, 250(1):71-90, 2002.
Akong K, Grevengoed E, Price M, McCartney BM, Hayden M, DeNofrio J and Peifer M. Drosophila APC2 and APC1 play overlapping roles in Wingless signaling in the embryo and imaginal discs. Developmental Biology, 250(1):91-100, 2002.
McCartney B, McEwen, Grevengoed E, Maddox P, Bejsovec A and Peifer M. Drosophila APC2 and Armadillo participate in tethering mitotic spindles to cortical actin. Nature Cell Biology, 3(10):933-938, 2001.
McCartney BM and Peifer M. Teaching tumour suppressors new tricks. Nature Cell Biology, 2(4): E58-E60, 2000.
McCartney BM, Dierick HA, Kirkpatrick C, Moline M, Baas A, Peifer M and Bejsovec A. Drosophila APC2 is a cytoskeletally-associated protein that regulates Wingless signaling in the embryonic epidermis. Journal of Cell Biology, 146(6):1303-1318, 1999.
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