Contact Information:
Research Interest
Mechanisms for micron-scale organization of vertebrate plasma membranes
Education
Stanford University: Chemical and biological studies; research with John Brauman; Phi Beta Kappa and National Chemistry Honorary Society; A.B., with "great distinction",1970
Johns Hopkins School of Medicine: Ph.D., "with distinction" mentored by Pedro Cuatrecasas: Adenylate Cyclase and the Mechanism of Action of Cholera Toxin; 1975
M.D., 1976
Harvard University: Postdoctoral training with Daniel Branton, Harvard University, 1976-77
Honors and Awards
Outstanding Young Scientist of the year in Maryland, 1982
HHMI investigator, 1987-2017
NIH Merit Award, 1990
Elected to American Society of Clinical Investigation, 1987; American Academy of Arts and Sciences, 2009; National Academy of Sciences, 2010; Association of American Physicians; American Association for the Advancement of Science, 2013.
National Service
Chair, Keystone Symposium Membrane-Cytoskeleton Interactions, 1985
Chair, Red Cell Gordon Research Conference 1987
NIH Hematology Study Section member: 1987-1992.
Co-Chair, Woods Hole Conference of the Society of General Physiologists,
Cytoskeletal Regulation of Membrane Function, 1996
Chair, Program committee for the 2009 American Society of Cell Biology meeting
Editorial boards: Journal of Biological Chemistry, 1990-95; Journal of Cell Biology
1997- 2019; Journal of Clinical Investigation, Associate editor 2012-2017
Mentoring
Vann has been fortunate to have contributed to the training of outstanding biomedical scientists, including Peter Agre (Director of Malaria Research Institute at Johns Hopkins; Nobel Prize in Chemistry, 2003); Kevin Gardner (Senior Vice Chair of Pathology and Cell Biology, Columbia); Velia Fowler (Chair of Biology, University of Delaware); David Virshup (Director of the Program in Cancer and Stem Biology at Duke-NUS Graduate Medical School); Peter Michaely (Assistant Professor, UT Southwestern); Lihsia Chen (Associate Professor, University of Minnesota); Peter Mohler (Professor, Chief Scientific Officer of Ohio State University); Jane Healy (Vice President and Head of Oncology Early Development, Merck); Paul Jenkins (Assistant Professor, University of Michigan); and Damaris Lorenzo (Associate Professor, University of Pennsylvania).
Functional Organization of Vertebrate Plasma Membranes: Molecules to Physiology
Plasma membrane proteins such as ion transporters, cell adhesion molecules, and signaling receptors all must segregate to specific cellular compartments to perform their physiological roles. Our laboratory has discovered ankyrin and adducin and their roles together with their partner spectrin in an adaptable mechanism that is responsible for coordinating functionally related membrane-spanning proteins within micron-scale domains in diverse vertebrate plasma membranes. These membrane domains include excitable membranes in the brain and heart, lateral membranes of epithelial cells, and costameres in striated muscle. Ankyrins recognize cytoplasmic domains of membrane transporters and cell adhesion proteins (15 protein families identified so far) through independently evolved interactions of intrinsically disordered sequences with a highly conserved peptide-binding groove formed by the ANK repeat solenoid. Ankyrins are coupled to spectrins, which are elongated organelle-sized proteins that form mechanically resilient arrays through crosslinking by specialized actin filaments capped on their fast growing ends by adducin. In addition, giant vertebrate ankyrins with specialized roles in the neurons acquired new coding sequences by exon shuffling early in vertebrate evolution. Loss of function mutations of ankyrins and spectrin result in human disease including hereditary anemia, cardiac arrhythmia, autism and neurodevelopmental disorders.
Selected Publications
182. Yang R, Walder-Christensen KK, Lalani S, Yan H, Garcia-Prieto D, Alvarez S, Fernandez-Jaen A, Speltz L, Jiang YH, Bennett V (2019). Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly. Proc Natl Acad Sci U S A. 116:19717-26; epub Aug 26, 2019.
181. Yang R, Walder-Christensen KK, Kim N, Wu D, Lorenzo DN, Badea A, Jiang YH, Yin HH, Wetsel WC, Bennett V (2019) ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity. Proc Natl Acad Sci U S A. 116(30):15262-15271. Epub Jul 8, 2019
173. Jenkins, PM, He, M, Bennett, V (2015) Motile spectrin/ankyrin-G microdomains promote lateral membrane assembly by opposing endocytosis. Science Advances e1500301.
172. Lorenzo DL, Healy JA, Hostettler J, Davis J, Yang J, Wang C, Hohmeier HE, Zhang M, Bennett V (2015) Ankyrin-B metabolic syndrome combines age dependent adiposity with pancreatic beta-cell insufficiency. J. Clin. Invest.125:3087-102
171. Tseng WC, Jenkins PM, Tanaka M, Mooney R, Bennett V. (2015) Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors. Proc Natl Acad Sci U S A. 112:12214-19
170. Jenkins PM, Kim N, Jones SL, Tseng WC, Svitkina TM, Yin HH, Bennett V. (2015) Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc Natl Acad Sci U S A. 112:957-64.
168. Lorenzo, DN, Badea, A, Davis, JQ, Hostettler, J, He, J, Zhong, G, Zhuang, X, Bennett, V (2014) A PIK3C3/Ankyrin-B/Dynactin pathway promotes axonal growth and multi-organelle transport. J Cell Biol. 207: 735-52.
163. He M, Abdi KM, Bennett V. (2014) Ankyrin-G palmitoylation and βII-spectrin binding to phosphoinositide lipids drive lateral membrane assembly. J Cell Biol. 206(2):273-88.
152. 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:ra19.
150. Kizhatil K, Baker SA, Arshavsky VY, Bennett V. (2009) Ankyrin-G promotes cyclic nucleotide-gated channel transport to rod photoreceptor sensory cilia. Science 323:1614-1617.
147. Ayalon, G., Davis, JQ., Scotland, P. and Bennett, V. (2008) An ankyrinbased mechanism for functional organization of dystrophin and dystroglycan. (2008) Cell 135:1189-1200.
144. Kizhatil, K., Davis, J.Q., Davis, L., Hoffman, J., Hogan, B.L. and Bennett, V. (2007) Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. J. Biol. Chem. 282: 26552-26561.
141. Pan, Z., Kao, T., Horvath, Z., Lemos, J., Sul, J.Y., Cranstoun, S.D., Bennett, V., Scherer, S.S. and Cooper, E.C. (2006) A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J. Neurosci. 26:2599-25613.
140. Lee, G., Abdi, K., Jiang, Y., Michaely, P., Bennett, V. and Marszalek, P. (2006) Nanospring behavior of ankyrin repeats. Nature 440: 246-249.
138. Mohler, P.J., Davis, J.Q. and Bennett, V. (2005) Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor in a cardiac T-tubule/SR Microdomain. Plos Biology 3:e423.
136. Ango, F., di Cristo, G., Higashiyama, H., Bennett, V., Wu, P, and Huang ZJ. (2004) Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segments Cell 119:257-272.
135. Mohler, P.J., Rivolta, I., Napolitano, C., LeMaillet, G., Lambert, S., Priori, S.G. and 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. 101:17533-17538.
133. Mohler, P.J., Splawski, I., Napolitano, C., Botteli, G., Sharpe, L., Timothy, K., Priori, S.G., Keating, M.T. and Bennett, V. (2004) A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat. Acad. Sci. USA 101:9137-9142.
Mohler, P.J., Schott, J.-J., Gramolini, A.O., Dilly, K.W., Guatimosim, S., duBell, W.H., Song, L.-S., Haurogne, K., Kyndt, F., Ali, M.E., Rogers, T.B., Lederer, W.J., Escande, D., Le Marec, H. and Bennett, V. (2003) Ankyrin-B mutation causes type 4 long-QT cardiac arrythmia and sudden cardiac death. Nature 421:634-639.
126. Mohler, P.J., Schott, J.-J., Gramolini, A.O., Dilly, K.W., Guatimosim, S., duBell, W.H., Song, L.-S., Haurogne, K., Kyndt, F., Ali, M.E., Rogers, T.B., Lederer, W.J., Escande, D., Le Marec, H. and Bennett, V. (2003) Ankyrin-B mutation causes type 4 long-QT cardiac arrythmia and sudden cardiac death. Nature 421:634-639.
120. Jenkins, S.M. and Bennett, V. (2001) Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments. J. Cell Biol. 155:739-46.
110. Zhou, D., Lambert, S., Malen, P.L., Carpenter, S., Boland, L.M. and Bennett, V. (1998) AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J. Cell Biol. 143:1295 1304.
99. Davis, J.Q., Lambert, S. and Bennett, V. (1996) Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J. Cell Biol. 135:1355-1367.
94. Kuhlman, P.A., Hughes, C.A., Bennett, V. and Fowler, V.M. (1996) A new function for adducin: calcium/calmodulin regulated capping of the barbed ends of actin filaments. J. Biol. Chem. 271:7986-7991.
87. Kordeli, E., Lambert, S. and Bennett, V. (1995) Ankyrin-G: a new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J. Biol. Chem. 270:2352-2359.
86. Davis, J. and Bennett, V. (1994) Ankyrin-binding activity shared by the neurofascin/L1/NrCam family of nervous system cell adhesion molecules. J. Biol. Chem. 269:27163-27166.
74. Kunimoto, M., Otto, E. and Bennett, V. (1991) A new 440-kDa isoform is the major ankyrin in neonatal rat brain. J. Cell Biol. 115:1319-1331.
63. Lux, S.E., John, K.M. and Bennett, V. (1990) Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue- differentiation and cell-cycle control proteins. Nature 344:36-42.
55. Srinivasan, Y., Elmer, L., Davis, J., Bennett, V. and Angelides, K. (1988) Ankyrin and spectrin associate with voltage-dependent sodium channels in brain. Nature 333:177-180.
51. Gardner, K. and Bennett, V. (1987) Modulation of spectrin-actin assembly by erythrocyte adducin. Nature 328:359-362.
41. Gardner, K. and Bennett, V. (1986) A new erythrocyte membrane-associated protein with calmodulin binding activity: identification and purification. J. Biol. Chem. 261:1339-1348.
40. Agre, P., Casella, J., Zinkham, W., McMillan, C. and Bennett, V. (1985) Erythrocyte spectrin is partially deficient in hereditary spherocytosis. Nature 314:380-383.
36. Davis, J. and Bennett, V. (1984) Brain ankyrin-a membrane associated protein with binding sites for spectrin, tubulin and the cytoplasmic domain of the erythrocyte anion channel. J. Biol. Chem. 259:13550-13559.
30. Bennett, V., Davis, J. and Fowler, W. (1982) Brain spectrin-a membrane associated protein related in structure and function to erythrocyte spectrin. Nature 299:126-131.
29. Agre, P., Orringer, E. and Bennett, V. (1982) Deficient red cell spectrin in severe, recessively inherited spherocytosis. New Engl. J. Med. 306:1155-1161.
20. Bennett, V. (1979) Immunoreactive forms of human erythrocyte Ankyrin are present in diverse cells and tissues. Nature 281:597-598.
19. Bennett, V. and Stenbuck, P. (1979) The membrane attachment site for spectrin is associated with band 3 in human erythrocyte membranes. Nature 280:468 473.
18. Bennett, V. and Stenbuck, P. (1979) Identification and partial purification of ankyrin, the high affinity membrane attachment site for human erythrocyte spectrin. J. Biol. Chem. 254:2533-2541.
16. Bennett, V. (1978) Purification of an active proteolytic fragment of the membrane attachment site for human erythrocyte spectrin. J. Biol. Chem. 253:2292-2299.