Lawrence B. Holzman, M.D.
Chief, Renal Electrolyte and Hypertension Division
Professor of Medicine
Perelman School of Medicine
University of Pennsylvania
Renal Electrolyte and Hypertension Division
415 Curie Boulevard, Suite 322 CRB
Philadelphia, PA 19104-4539
Undergraduate: University of Pennsylvania, Philadelphia, PA
Medical: UMDNJ – New Jersey Medical School, Newark, NJ
Residency: Hospital of the University of Pennsylvania, Philadelphia, PA
Fellowship: University of Michigan Hospital, Ann Arbor, MI
Board Certification: Internal Medicine and Nephrology
Synopsis: Dr. Holzman is Professor of Medicine and Chief of the Renal-Electrolyte and Hypertension Division at the University of Pennsylvania. His clinical work focuses on inflammatory and non-inflammatory glomerular disease of the kidney. He is an established laboratory investigator interested in the mechanisms that govern podocyte cytoskeletal architecture and the signaling mechanisms that determine the functional specificity of the JNK module and the mitogen activated protein 3 kinase, DLK.
Basic Science: The Holzman lab conducts studies in two areas that are described briefly below.
A. The Holzman lab studies the biochemistry and function of DLK, a member of the mixed lineage kinase family of MAPK 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. Therefore, DLK participates in a specific JNK module that regulates insulin sensitivity. The lab is particularly focused on understanding the critical mechanisms that govern JNK signaling specificity and activation. In its most important contribution to this area, the lab established that the DLK associated JIP1 scaffold serves as a signaling nexus for multiple signaling pathways that is regulated by phosphorylation events on JIP1.
B. 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 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.
Clinical Science: With Drs. Matthias Kretzler and Akinlolu Ojo at the University of Michigan, Dr. Holzman founded NEPTUNE, an international consortium of academic medical centers for the clinical investigation of patients presenting with nephrotic syndrome including patients with steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis and membranous nephropathy. This organization has initiated studies aimed initially at the identification of biomarkers that might better classify glomerular disease in a manner that might predict disease natural history or response to therapeutic intervention.
Clinical and Other Interests:
Clinical care: Dr. Holzman is known among his patients and colleagues for his compassionate, thoughtful, and thorough care. He is an expert in the care of patients with glomerular disease, particularly those with lupus nephritis, systemic small vessel vasculitis, and other inflammatory glomerular diseases. Before moving to the University of Pennsylvania in 2009, he shared for many years a specialized lupus and vasculitis clinic with rheumatologist Dr. Joseph McCune at the University of Michigan. He is referred complex glomerular disease patients from around the region. At Penn, along with members of the Rheumatology Division, he has established a joint rheumatology/nephrology clinic for the care of patients with lupus or small vessel vasculitis. He has been recognized as one of the “Best Doctors in America” since 2004 and is asked to lecture on glomerular disease both locally and as an invited speaker and visiting professor nationally.
Service: As part of his effort to promote the welfare of his patients and research and advocacy in the area of glomerular disease, Dr. Holzman works closely with the Nephcure Foundation (www.nephcure.org) and serves as chairperson of its scientific advisory board. In this role, Dr. Holzman created and now steers Nephcure’s extramural grant program, has lobbied the NIH and Congress, and has testified before the US Senate committee for NIH appropriations. He has served the National Kidney Foundation as a member of its Science Committee and as a member of the advisory panel to the Lupus Alliance (Michigan Chapter). Presently he serves the American Society of Nephrology as a member of its grant review committee and as a member of its nominating committee. Dr. Holzman has also served the research community principally as a member of multiple study sections, including a four year commitment as a regular member of an NIH study section.
I. DLK, JIP1, JNK biolog
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, 1994; 269(49):30808-30817.
As its title implies, this paper represents the initial discovery and description of DLK, a member of the mixed lineage kinase family of mitogen activated protein-3 kinases. This work forms the foundation of Dr. Holzman's longstanding interest in the biochemistry and function of this protein and the JNK module.
Fan, G., Merritt, S., Kortejann, M., Shaw, P., Holzman, L.B. DLK activates SAPK and p38mapk but not ERK2. J Biol Chem, 1996; 271(40):24788-24793.
This paper describes the first recognition that DLK was a MAP3K, an upstream kinase in the MAPK pathway leading to JNK and/p38mapk activation. The work was particularly important because for the first time, it placed the mixed lineage kinase group f kinases in MAPK modules.
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. 2001 20(13):3447-58.
This paper presents the seminal observation that beyond merely assembling the three component kinases of the JNK module, the scaffold protein JIP1 functions to regulate the activation of this pathway in a dynamic and complex fashion. The work altered our view of the nature MAPK complexes, the details of which remain under investigation by Dr. Holzman’s group and others.
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. 2003 Aug 1;278(31):28694-702. Epub 2003 May 19.
This paper clarifies the mechanism by which the scaffold protein JIP1 integrates the regulation of the JNK module. Beyond mapping the serine and threonine residues that are phosphorylated on JIP1, this work demonstrated that JNK is recruited to and phosphorylates JIP1 on T103; as a result, DLK dissociates from JIP1, oligomerizes, and becomes auto-activated before activating the downstream components of the JNK module.
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.
This paper describes the observation that JIP1 is tyrosine phosphorylated by Src Family Kinases. The paper is important because it established that JIP1 is a scaffold protein that serves as a nexus that integrates signaling from a variety of signaling pathways that is regulated by multiple functionally necessary JIP1 phosphorylation events.
II. Podocyte Biology
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 International, 1999 Oct 13;56(4):1481-1491.
This frequently cited paper describes the cloning and initial characterization of mouse nephrin. The paper showed that nephrin is targeted to the podocyte intercellular junction and that during podocyte development, that nephrin is first expressed and targeted to processes that emerge from the baso-lateral aspect of the podocyte precursor.
Moeller MJ, Sanden SK, Soofi A, Wiggins RC, Holzman LB. Two gene fragments that direct podocyte-specific expression in transgenic mice. J Am Soc Nephrol 2002 Jun;13(6):1561-67.
This paper is representative of a series of papers in which the technology for genetically manipulating the podocyte in mice in a cell- and temporal-specific fashion was developed. As a result of this work, mice expressing Cre recombinase in a podocyte-specific fashion have now been exported to nearly 50 labs internationally for investigations of the podocyte. A colony of these animals has also been established a Jackson Labs.
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. 2003 Jun 6;278(23):20716-23. Epub 2003 Mar 31.
This paper uses both biochemical and genetic methods in mice to demonstrate that the Src Family Kinase Fyn is a component of the nephrin junctional complex and tyrosine phosphorylates nephrin.
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):3769-79. Epub 2004 Sep 02.
The mechanisms that determine the regulation of cellular motility and junction formation remain incompletely understood. This paper represents the first description of the cell biological properties of the atypical cadherin FAT1. This work places FAT1 at sites of rapid actin turnover at the leading edge of lamellipodia and in filopodia where it is necessary for normal actin dynamics and for establishing cell polarity in the plane of the tissue. The work is applicable to the investigation of the podocyte and was initially undertaken when another group showed that FAT1 is present at the podocyte intercellular junction. The observations made fit well with Dr. Holzman's focus on identifying mechanisms that integrate podocyte junctional integrity and podocyte cytoskeletal dynamics.
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.
This manuscript describes the observation that upon nephrin ligation, nephrin is tyrosine phosphorylated on specific residues, recruits the adaptor protein Nck, and initiates actin filament nucleation and elongation. This work established for the first time that the nephrin protein complex functions to transduce signals from the podocyte intercellular junction to regulate the podocyte actin cytoskeleton.
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.
Extending observations made in manuscript #10, this paper found that like nephrin, neph1 is tyrosine phosphorylated following ligation, recruits the adaptor Grb2, and subsequently induces actin polymerization. In addition, this paper demonstrated that nephrin and neph1 form a synergistic complex that regulates actin polymerization.