04/08 - present    Assistant Professor of Medicine, Miller School of Medicine, University of Miami, Department of 
                            Medicine

12/06 – 03/08      Assistant Professor of Medicine, Mount Sinai School of Medicine, New York, Division of Nephrology

09/05 – 11/06      Postdoctoral Fellow, Mount Sinai School of Medicine, New York, laboratory of Dr. Peter Mundel,
                            Department of Medicine

09/01 – 09/05      Graduate student and PhD candidate, Albert Einstein College of Medicine, New York, laboratory of
                            Dr. Peter Mundel, Department of Anatomy and Structural Biology

03/00 - 08/01       Visiting Scientist, Albert Einstein College of Medicine, New York, laboratory of Dr. Peter Mundel

10/97 – 12/98       Diploma student, Max Planck Institute for Medical Research, Heidelberg, Germany, laboratory of
                             Prof. Peter Seeburg, Department of Molecular Neurobiology

06/96 – 08/96       Research Assistant, German Cancer Research Center, Heidelberg, Germany, laboratory of Prof.
                             Guenther Haemmerling, Department of Molecular Immunology

1995 -1996           Research Assistant, Ruprecht Karls University, Heidelberg, Germany, laboratory of Prof. Wilhelm
                             Kriz, Department of Anatomy and Cell Biology

 

The Z-disc as a signaling complex in cardiac myocytes

The Z-disc is a multiprotein complex which forms the lateral boundaries of the sarcomer, the contractile unit of striated muscle. The Z-disc serves as an anchor for actin filaments and links the plasma membrane to the contractile machinery. For along time it was assumed that the passive transmission of force generated within the myofilament system is the main function of the Z-disc.

With the recent discovery of multiple novel proteins as Z-disc components it became obvious that the Z-disc has not only structural and scaffolding functions, but also participates in signal transduction events. In fact, multiple signaling molecules including protein kinases and phosphatases, phosphodiesterases and small GTPases were linked to the Z-disc. Some signaling proteins are in dynamic exchange between the Z-disc and the cytoplasm, display variable sarcomeric locations and shuttle between the Z-disc and the nucleus. The dynamic relocation of Z-disc proteins in response to stress or extracellular signals suggests that the Z-disc creates a giant communicative network that integrates signals from various origins. In cardiac myocytes, the Z-disc serves as a mechanosensor during cardiac remodeling. Mounting evidence supports the notion that the Z-disc can sense an increase in mechanical load and communicate with the nucleus to induce changes in gene expression, which in turn result in cardiac hypertrophy and increased cardiac output.

A major focus of our work is on the functional characterization of myopodin. Myopodin is a dual-compartment, actin-bundling protein that shuttles between the nucleus and the Z-disc of myocytes in a differentiation- and stress-dependent fashion. Under stress conditions, myopodin is depleted from the Z-disc and re-enters the nucleus. Recently we reported that importin a binding and subsequent nuclear import of myopodin are regulated by the serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. Additionally, we showed that myopodin participates in intracellular signal transduction between the Z-disc and the nucleus of differentiated adult cardiac myocytes. This pathway is regulated by the protein kinases PKA and CaMKII and the protein phosphatase calcineurin. When myopodin is phosphorylated, 14-3-3 competes with a-actinin for binding to myopodin and causes the release of myopodin from its Z-disc anchor a-actinin and the subsequent nuclear import. These findings make myopodin a promising candidate to function as a signal mediator between the Z-disc and the nucleus. We hypothesize that myopodin can link stress-induced changes within the sarcomeric structure to alterations in gene expression.

Future experiments will include the identification of upstream stimuli and signaling molecules (G-protein coupled receptors, Ca2+-channels, protein kinase anchoring proteins etc.) that regulate PKA, CaMKII and calcineurin activity and thereby the subcellular localization of myopodin in cardiac myocytes. Additionally, the functional consequence of nuclear myopodin will be studied with focus on a potential influence on apoptosis and the regulation of hypertrophic gene programs. 

The slit diaphragm as a signaling unit that regulates the actin cytoskeleton in renal podocytes

Podocytes consist of three morphologically and functionally different segments: a cell body, major processes, and foot processes (FPs). From the cell body major processes arise that split into FPs. The FPs contain an actin-based cytoskeleton that is linked to the glomerular basement membrane (GBM) in focal contacts. Podocyte FPs form a highly branched interdigitating network with FPs of neighboring podocytes connected by the slit diaphragm (SD), a multi-protein complex similar to adherens junctions. The SD covers the filtration slits (regions between opposing podocyte FPs), thereby establishing the final barrier to urinary protein loss. FPs are further characterized by a podosome-like, cortical network of short branched actin filaments and the presence of highly ordered contractile actin filament bundles which are thought to modulate the permeability of the filtration barrier through changes in FP morphology.

The SD represents a complex signal transduction unit that spans the 30-50 nm wide filtration slits. The extracellular portion of the SD is made up of rod-like units connected in the center to a linear bar forming a zipper-like pattern with pores the same size as or smaller than albumin. So far over 20 proteins have been identified as SD components. Some of those are transmembrane proteins serving as cell-cell adhesion molecules, cell surface receptors or SD organizers. Other SD proteins function as adaptor proteins that link the SD physically and functionally to the underlying actin filaments. Another set of SD proteins represent signaling molecules that translate changes in the SD to alterations in actin polymerization and possibly gene expression. The biochemical complexity of the SD protein network most likely reflects a SD function that is far more complex than simply serving as a physical sieve. The SD may function as a key sensor and regulator of the permanent changes in FP shape and length. Of note, the dysregulation of the SD or its loss is a common theme in many renal diseases.

Our laboratory is studying the SD by identifying novel components of the SD protein complex, analyzing their biochemical features and characterizing their functions in cell culture and animal models. We are focusing on protein kinases and phosphatases and their target proteins that communicate with the actin cytoskeleton and the nucleus. The recent identification of a selective calcium channel at the SD suggests that calcium might serve as a second messanger at the SD. We hypothesize that the regulated calcium entry at the SD may control podocyte FP dynamics and cell behavior and that the detection of calcium influx at the SD requires the presence of calcium and calmodulin binding proteins. Future studies will show if such proteins are present at the SD and capable to translate local changes in calcium levels into changes of actin dynamics and gene expression.

 

Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgauuw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P. The actin cytoskeleton of kidney podocytes is a direct target of the anti-proteinuric effect of cyclosporine A. Nat Med. 2008, 14: 931-8

Krick S, Shi S, Ju W, Faul C, Tsai S, Mundel P, Boettinger E. Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease. Proc Natl Acad Sci U S A. 2008, 105: 14106-11.

Faul C, Dhume A, Schecter A, Mundel P. PKA, CaMKII and calcineurin regulate the intracellular trafficking of myopodin between the Z-disk and the nucleus of cardiac myocytes. Mol Cell Biol. 2007, 27: 8215-27

Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007, 17: 428-37

Yanagida-Asanuma E, Asanuma K, Kim K, Donnelly M, Young Choi H, Hyung Chang J, Suetsugu S, Tomino Y, Takenawa T, Faul C, Mundel P. Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am J Pathol. 2007, 171: 415-27

Asanuma K, Campbell KN, Kim K, Faul C, Mundel P. Nuclear relocation of the nephrin and CD2AP binding protein dendrin promotes apoptosis of podocytes. Proc Natl Acad Sci U S A. 2007, 104: 10134-9

Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006, 8: 485-91.

Reiser R, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005, 37: 739-44.

Faul C, Hüttelmaier S, Oh J, Hachet V, Singer RH, Mundel P. Promotion of importin a mediated nuclear import by phosphorylation dependent binding of cargo protein to 14-3-3. J Cell Biol. 2005, 169: 415-24.

Asanuma K, Kim K, Oh J, Giardino L, Chabanis S, Faul C, Reiser J, Mundel P. Synaptopodin regulates the actin-bundling activity of a-actinin in an isoform-specific manner. J Clin Invest. 2005, 115: 1188-98.

Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004, 113: 1390-7.

Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest. 2001, 108: 1621-9.

Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol. 2001, 155: 393-404.

View published research articles by Dr. Faul in the National Library of Medicine