Faul Laboratory

General information

Christian Faul, Ph.D.
Assistant Professor, Medicine / Nephrology
Assitant Professor, Cell Biology and Anatomy

Research Interests

• Calcineurin signaling in podocytes
• The Z-disc as a stress sensor in striated myocytes 
• The slit diaphragm as a signaling unit in renal podocytes

Keywords and Phrases

• Myopodin and its function as a signal mediator between Z-disc and nucleus in cardiac myocytes
• Myopodin and its role in skeletal muscle development
• Myopodin as a tumor suppressor that regulates cell proliferation and apoptosis
• Calcineurin, CaMKII and PKA as regulators of the actin cytoskeleton in renal podocytes
• Induction of proteinuria by changes in the podocyte actin cytoskeleton

Contact Information

• Office location: Batchelor Bldg., 6th Fl, Room 628 (R-762)
  1580 NW 10th Avenue
  Miami, FL 33136
• Tel: (305) 243-3206
• Lab Location: Batchelor Bldg. 6th Fl (R-762),
  1580 NW 10th Avenue
  Miami, FL 33136
• Tel: (305) 243-6588
• Fax: (305) 243-4338
• E-mail: CFaul@med.miami.edu

Members

Research

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. 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 phosphates 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 and 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 podocyte actin dynamics
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 which covers the filtration slits (regions between opposing podocyte FPs), thereby establishing the final barrier to urinary protein loss. The SD represents a complex signal transduction unit which 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.

Selected Publications

• Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw 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: 931-9388. Published online: 24 August 2008
• 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
• 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.
• 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.