Faculty Profile

Vann Bennett, M.D., Ph.D.
(Johns Hopkins School of Medicine)

James B. Duke Professor, Departments of Cell Biology, Biochemistry, and Neurobiology

Investigator, Howard Hughes Medical Institute

Programs: CMB, Molecular Cancer Biology

Functional organization of membrane-spanning proteins in vertebrate tissues
Membrane-spanning proteins such as ion transporters, cell adhesion molecules, and signaling receptors all must segregate to specific cellular locations to perform their physiological roles in our bodies. Deciphering the molecular basis for plasma membrane polarity is an interdisciplinary problem at the interface of cell biology, physiology, and clinical medicine. Our laboratory has discovered the ankyrin family of adapters and their role in the organization of a surprisingly diverse set of proteins and membrane domains that are likely to play pervasive roles in vertebrate physiology. We have resolved a simple "code" for ankyrin binding by membrane proteins that has independently evolved in many protein families, including those such as voltage-gated sodium channels with specialized roles in vertebrates. We have found that ankyrin proteins are required for coordination of functionally related membrane partners within specialized membrane domains, including axon initial segments of neurons, lateral membrane domains of epithelial cells, inner and outer segments of photoreceptors, and costameres of striated muscle. We are exploring the molecular mechanisms underlying ankyrin function as well as the pathological consequences—such as cardiac arrhythmia and diabetes—when these mechanisms fail.

E-mail
benne012@mc.duke.edu

361 CARL Building
Box 3892 Duke University Medical Center
Durham, NC 27710

Telephone
919-684-3538, 919-684-3105
Fax
919-684-3590

Selected Publications
Healy JA, Nilsson KR, Hohmeier HE, Berglund J, Davis J, Hoffman J, Kohler M, Li LS, Berggren PO, Newgard CB, Bennett V (2010) Cholinergic augmentation of insulin release requires ankyrin-B. Sci Signal. 3(113):ra19. -PDF-

Sobotzik JM, Sie JM, Politi C, Del Turco D, Bennett V, Deller T, Schultz C (2009) Ankyrin-G is required to maintain axo-dendritic polarity in vivo. Proc Natl Acad Sci U S A. 106:17564-9. -PDF-

Kizhatil K, Baker SA, Arshavsky VY, Bennett V (2009) Ankyrin-G promotes cyclic nucleotide-gated channel transport to rod photoreceptor sensory cilia. Science. 323:1614-7. -PDF-

Kizhatil K, Sandhu NK, Peachey NS, Bennett V (2009) Ankyrin-B is required for coordinated expression of beta-2-spectrin, the Na/K-ATPase and the Na/Ca exchanger in the inner segment of rod photoreceptors. Exp Eye Res. 88:57-64. -PDF-

Davis L, Abdi K, Machius M, Brautigam C, Tomchick DR, Bennett V, Michaely P (2009) Localization and structure of the ankyrin-binding site on beta2-spectrin. J Biol Chem. 284:6982-7. -PDF-

Ayalon, G, Davis, JQ, Scotland, P, Bennett V (2008) An ankyrin-based mechanism for functional organization of dystrophin and dystroglycan. Cell. 135:1189-2000. -PDF-

Bennett V, Healy J. (2008) Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol Med. 14(1):28-36. -PDF-

Abdi KM, Bennett V. (2008) Adducin Promotes Micrometer-Scale Organization of {beta}2-Spectrin in Lateral Membranes of Bronchial Epithelial Cells. Mol Biol Cell. 19(2):536-45. -PDF-

Mohler PJ, Healy JA, Xue H, Puca AA, Kline CF, Allingham RR, Kranias EG, Rockman HA, Bennett V. Ankyrin-B syndrome: enhanced cardiac function balanced by risk of cardiac death and premature senescence. (2007) PLoS ONE. 2(10):e1051. -PDF-

Kizhatil K, Davis JQ, Davis L, Hoffman J, Hogan BL, Bennett V. (2007) Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. J Biol Chem. 282(36):26552-61. -PDF-

Kizhatil K, Yoon W, Mohler PJ, Davis LH, Hoffman JA, Bennett V. (2007) Ankyrin-G and beta2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells. J Biol Chem. 282(3):2029-37. -PDF-

Lee G, Abdi K, Jiang Y, Michaely P, Bennett V, Marszalek PE. (2006) Nanospring behaviour of ankyrin repeats. Nature. 440:246-9. -PDF-

Mohler, PJ, Davis, JQ, Bennett, V. (2005) Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor in a specialized microdomain of cardiac T-tubules. Plos Biology. 3:e423. -PDF-

Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. (2004) Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci USA. 101:17533-8. -PDF-

Mohler, P. J et al. (2003) Ankyrin-B mutation causes type 4 long QT cardiac arrhythmia and sudden cardiac death. Nature. 421:634-639. -PDF-

Future Directions
Our current research addresses several general questions:

1) Mechanisms underlying ankyrin-dependent membrane domain biogenesis. Experimental models for these studies: a) cultured human bronchial epithelial cells where ankyrin-G and beta-2 spectrin are required for biogenesis of the lateral membrane; b) skeletal muscle where ankyrin-B and -G collaborate with microtubules in localization of dystrophin at costameres and neuromuscular junctions. c) axon initial segmens of neurons where ankyrin-G functions as a master organizer.

2) Role of ankyrins/spectrins in organizing and responding to signaling including the TGF-beta pathway.

3) Role of ankyrin-B in aging-related diseases in humans and mice. We have found that ankyrin-B (+/-) mice have reduced life-span and exhibit accelerated senescence in multiple tissues. We also have found that loss-of-function mutations in ankyrin-B are surprisingly common in human populations (2 percent of Europeans). Our working model is that these human ankyrin-B mutations represent balanced polymorphisms with benefits (increased cardiac performance) balanced by costs (risk of sudden cardiac death and reduced life span). At a clinical level, we are exploring roles of ankyrin-B in aging-related diseases including diabetes, where we have identified an ankyrin-B mutation as a risk factor. In addition, we are developing mouse models with knock-in of two of the human ankyrin-B variants.

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