Research Summary:

This lab studies the biochemistry and function of DLK and other members of the mixed lineage kinase family of MAP3K. The lab identified DLK and first showed that it is capable of differentially activating the mitogen activated protein kinases, JNK and p38mapk. The lab is interested in understanding the mechanisms that govern JNK signaling specificity and activation. Ongoing work is aimed at refining a model of DLK-dependent JNK module regulation by dissecting structure-function relationships, by identifying specific DLK interacting proteins, and by identifying physiological functions for DLK. We also study the biology of the podocyte by characterizing the molecular components of its specialized intercellular junction. We are testing the hypothesis that these junction components participate in maintaining the integrity of the glomerular filter and in regulating podocyte morphology by modulating cytoskeletal dynamics. The lab focuses on Nephrin, FAT1, and on src kinase mediated signaling from these receptors.

Link to PubMed Citations

Selected Publications:

Garg, Puneet, Verma, R., Nihalani, D, Holzman, LB. Nephrin and Neph1 form a signaling complex and cooperate to regulate actin polymerization. Mol Cell Biol. 2007 Dec;27(24):8698-712. Epub 2007 Oct 8.

Braun GS, Kretzler M, Heider T, Floege J, Holzman LB, Kriz W, Moeller MJ Differentially spliced isoforms of FAT1 are asymmetrically distributed within migrating cells. J Biol Chem. 2007 Aug 3;282(31):22823-33. Epub 2007 May 11.

Harvey SJ, George Jarad, Jeanette Cunningham, Angelique L. Rops, Johan van der Vlag, Jo H. Berden, Marcus J. Moeller, Lawrence B. Holzman, Robert W. Burgess , and Jeffrey H. Miner. Disruption of Glomerular Basement Memebrane Charge Through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity. Am J Pathol. 2007 Jul;171(1):139-52.

Garg, Puneet, Rakesh Verma, and Lawrence B. Holzman . Slit diaphragm junctional complex and regulation of the cytoskeleton. Nephron Exp Nephrol. 2007;106(2):e67-72. Epub 2007 Jun 6.

Suleiman, Hani, Daniel Heudobler, Irmgard Hertting, Helga Vitzthum, Marcus J. Moeller, Yuan Zhuang, Randy Johnson, Heiner Westphal, Lawrence B. Holzman, Reinhard Rachel, Anne Rascle, Ralph Witzgall. The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes. Dev Biol. 2007 Apr 15;304(2):701-12. Epub 2007 Jan 18.

Reddy GR, Pushpanathan MJ, Ransom RF, Holzman LB, Brosius FC 3rd, Diakonova M, Mathieson P, Saleem MA, List EO, Kopchick JJ, Frank SJ, Menon RK. Identification of the glomerular podocyte as a target for growth hormone action. Endocrinology. 2007 May;148(5):2045-55. Epub 2007 Feb 1.

Nihalani, Deepak, Hetty Wong, Rakesh Verma, Lawrence B. Holzman . Src Family Kinases Directly Regulate JIP1 Module Dynamics and Activation. Mol Cell Biol. 2007 Apr;27(7):2431-41. Epub 2007 Jan 22.

Bernward Hinkes, Roger C. Wiggins, Rasheed Gbadegesin, Christopher Vlangos, Dominik Seelow, Gudrun Nurnberg, Puneet Garg, Rakesh Verma, Hassan Chaib, Bethan E. Hoskins, Shazia Ashraf, Christian Becker, Hans Christian Hennies, Meera Goyal, Bryan Wharram, Asher Schachter, Iain Drummond, Dontscho Kerjaschki, Rudiger Waldherr, Alexander Dietrich, Grant C. Kelley, Fatih Ozaltin, Aysin Bakkaloglu, Roxana Cleper, Lina Basel, Martin Pohl, Martin Griebel, Alexander N. Tsygin, Alper Soylu, Dominik Muller, Mathilda Katan, Jinhong Liu, Massimo Attanasio, John F. O’Toole, Katrin Hasselbacher, Bettina Mucha, Edgar A. Otto, Rannar Airik, Andreas Kispert, Alan Smrcka, Thomas Gudermann, Lawrence B. Holzman, Peter Nurnberg, & Friedhelm Hildebrandt. Positional cloning of PLCE 1 mutations as the first cause of a nephrotic syndrome variant which may be reversible . Nat Genet. 2006 Dec;38(12):1397-405. Epub 2006 Nov 5.

El-Aouni C, Herbach N, Blattner SM, Henger A, Rastaldi MP, Jarad G, Miner JH, Moeller MJ, St-Arnaud R, Dedhar S, Holzman LB, Wanke R, Kretzler M. Podocyte-Specific Deletion of Integrin-Linked Kinase Results in Severe Glomerular Basement Membrane Alterations and Progressive Glomerulosclerosis. J Am Soc Nephrol. 2006 May;17(5):1334-44. Epub 2006 Apr 12.

Verma, R, Kovari, I, Abdul S, Nihalani D, Patrie K, and Holzman LB. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006 May;116(5):1346-59. Epub 2006 Mar 16.

Johnstone DB, and Holzman LB. Clinical impact of research on the podocyte slit diaphragm. Nature Clinical Practice Nephrology (2006) 2, 271-282.

Wharram BL, Goyal M, Wiggins JE, Sanden SK , Hussain S, Filipiak WE, Saunders TL, Dysko, RC, Kohno K, Holzman LB, Wiggins RC: Podocyte depletion causes glomerulosclerosis. Diphtheria toxin-induced podocyte depletion in rats expressing the human DTR transgene. J Am Soc Nephrol. 2005 Oct;16(10):2941-2952. Epub 2005 Aug 17

Oetjen E, Lechleiter A, Blume R, Nihalani D, Holzman L, Knepel W. Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein ( CREB ) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line. Diabetologia. 2006 Feb;49(2):332-342. Epub 2005 Dec 21.

McCune WJ, Saluja M, Bhat S, Lange LA, Holzman L, and Johnson K. Correlation of membranous glomerular ultrastructural changes with disease severity and outcome in lupus patients initiating cyclophosphamide therapy. Lupus 2005 14:426-433.

Moeller MJ, Abdulsalam Soofi, Silja Sanden, Jürgen Floege, Wilhelm Kriz, and Holzman LB. An efficient system for tissue-specific over-expression of transgenes in podocytes in vivo. Am J Physiol Renal Physiol. 2005 Aug;289(2):F481-F488. Epub 2005 Mar 22

Moeller, MJ, Soofi, A, Watzel, C, Kriz, W, and Holzman LB. Protocadherin FAT1 binds Ena/VASP and is necessary for lamellipodial dynamics, cell polarization, and cell migration. EMBO J. 2004 Sep 29;23(19):3769-3779. Epub 2004 Sep 02.

Schiwek D, Endlich N, Holzman L, Holthofer H, Kritz W, Endlich K. Stable expression of Nephrin and localization to cell-cell contacts in novel murine podocyte cell lines. Kidney Int. 2004 Jul;66(1):91-101.

Moeller MJ, Soofi A, Hartmann I, Wiggins R, Le Hir M, Kriz W, and Holzman LB. Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J Am Soc Nephrol, 2004 Jan;15(1):61-67.