Dr. Holzman is an established and NIH funded laboratory investigator, well recognized for his investigations of mechanisms of cell signaling and also of podocyte biology, where he has contributed importantly to our understanding of the mechanisms that govern podocyte cytoskeletal architecture.
The Holzman lab studies the biochemistry and function of DLK, a member of the mixed lineage kinase family of MAPK kinase kinases. The laboratory initially discovered and cloned DLK and first demonstrated that DLK is a MAP3 kinase capable of activating the mitogen activated protein kinase family of JNK kinases. It showed that DLK is activated by insulin and in soon to be published work demonstrated that deletion of DLK in mice results in a phenotype of resistance to diet induced obesity and cell autonomous increased insulin sensitivity.
Dr. Holzman also investigates the biology of the glomerular podocyte, a unique epithelial cell that appears to play a central role in most forms of glomerular disease. The octopus-like processes of the podocyte interdigitate and form specialized intercellular junctions that function as the kidney glomerular filter. The lab has been a leader in characterizing the molecular components of this intercellular junction and first established evidence to support the hypothesis that these junctional components participate in regulating podocyte morphology by modulating actin cytoskeletal dynamics. The lab has particularly focused on signaling functions of members of the cell adhesion molecules of the Nephrin family and has contributed seminal work on the atypical cadherin FAT1. As part of this work, the lab has developed a transgenic mouse strategy for examining the functional biology of proteins and their interactions specifically in the podocyte that is now used internationally.
Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PXK, Barisoni L, Sampson MG, Kopp JB, Lemley KV, Nelson PJ, Lienczewski CC, Adler SG, Appel GB, Cattran DC, Choi MJ, Contreras G, Dell KM, Fervenza FC, Gibson KL, Greenbaum LA, Hernandez JD, Hewitt SM, Hingorani SR, Hladunewich M, Hogan MC, Hogan SL, Kaskel FJ, Lieske JC, Meyers KEC, Nachman PH, Nast CC, Neu AM, Reich HN, Sedor JR, Sethna CB, Trachtman H, Tuttle KR, Zhdanova O, Zilleruelo GE, Kretzler M: Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int 83(4): 749-56, Apr 2013.
George B, Verma R, Soofi AA, Garg P, Zhang J, Park T, Giardino L, Ryzhova L, Johnstone DB, Wong H, Nihalani D, Salant DJ, Hanks SK, Curran T, Rastaldi MP, and Holzman LB: Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mice. J Clin Invest 122(2): 674-92, Feb 2012.
Johnstone DB, Zhang J, George B, Léon C, Gachet C, Wong H, Parekh R, Holzman LB: Podocyte-specific deletion of Myh9 encoding non-muscle myosin heavy chain 2A predisposes mice to glomerulopathy. Mol Cell Biol 31(10): 2162-70, Mar 2011 Notes: [Epub ahead of print]
Garg P, Verma R, Nihalani D, Johnstone DB, Holzman LB: Neph1 cooperates with Nephrin to transduce a signal that induces actin polymerization. Mol Cell Biol 27(24): 8968-712, 2007.
Nihalani D, Wong HN, Rakesh V, Holzman LB: Src family kinases directly regulate JIP1 module dynamics and activation. Mol Cell Biol 27(7): 2431-41, 2007.
Verma R, Kovari I, Abdul S, Nihalani D, Patrie K, Holzman LB: Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest 116(5): 1346-1359, 2006.
Moeller MJ, Soofi A, Hartmann I, Wiggins R, Le Hir M, Kriz W, Holzman LB: Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis. J Am Soc Nephrol 15(1): 61-67, Jan 2004.
Moeller MJ, Soofi A, Watzel C, Kriz W, Holzman LB : Protocadherin FAT1 binds Ena/VASP and is necessary for lamellipodial dynamics, cell polarization, and cell migration. EMBO J 23(19): 3769-3779, Oct 2004.
Holzman LB, Merritt S, Fan G: Identification, molecular cloning, and characterization of Dual Leucine Zipper Kinase: a novel serine/threonine kinase that defines a second subfamily of MLK kinases. J Biol Chem 269(49): 30808-30817, 1994.
Fan G, Merritt S, Kortejann M, Shaw P, Holzman LB: DLK activates SAPK and p38mapk but not ERK2. J Biol Chem 271(40): 24788-24793, 1996.
Holzman LB, St. John P, Kovari I, Verma R, Holthofer H, Abrahamson D: Nephrin is localized to the slit pore of the glomerular epithelial cell. Kidney Intl 56(4): 1481-1491, 1999.
Moeller M, Kovari IA, Holzman LB: Evaluation of a new tool for exploring podocyte biology: Mouse Nphs1 5' flanking region drives lacZ expression in podocytes. J Am Soc Nephrol 11: 2306-2314, 2000.
Nihalani D, Meyer D, Pajni S, Holzman LB: Mixed lineage kinase-dependent JNK activation is governed by interactions of scaffold protein JIP with MAPK module components. EMBO J 20(13): 3447-3458, 2001.
Schwarz K, Reiser J, Kriz W, Shaw A, Kerjascki D, Holzman LB, Mundel P: Podocin, a stomatin-like protein linked to steroid-resistant nephrotic syndrome, is a raft-associated component of the glomerular slit diaphragm that interacts with CD2AP and nephrin. J Clin Invest 108(11): 1621-1629, 2001.
Barletta GM, Kovari IA, Verma RK, Nihalani D, Holzman LB: Nephrin and Neph1 co-localize at the podocyte foot process intercellular junction and form cis hetero-oligomers. J Biol Chem 278(21): 19266-19271, May 2003.
Rakesh V, Wharram B, Kovari I, Riggs L, Nihalani D, Wiggins R, Killen P, Holzman LB: Fyn binds to and phosphorylates the slit diaphragm component Nephrin. J Biol Chem 278(23): 20716-20723, Jun 2003.
Nihalani D, Wong H, Holzman LB: Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylation regulates JNK module dynamics and activation. J Biol Chem 278(31): 28694-28702, Aug 2003.
back to top
Last updated: 09/26/2014
The Trustees of the University of Pennsylvania