Lewis Jacobson

  • Professor
  • Signal transduction

Contact

Office: (412) 624-4647
Lab: (412) 624-4647
A527A Langley Hall
4249 Fifth Avenue
Pittsburgh, PA 15260

´╗┐Dr. Jacobson's laboratory is interested in the physiological and hormonal factors that control the degradation of proteins in muscle. Abnormally rapid muscle protein degradation is associated with various disease states that lead to muscle wasting or muscle atrophy, including cancer, sepsis, AIDS, renal failure, diabetes and chronic inactivity. The nematode Caenorhabditis elegans is used as a model organism for these studies, because of the exceptional convenience of genetic manipulation and analysis and the overall cellular simplicity of the animal. Over the past few years, our work has shown that muscle protein degradation is regulated by diverse networked signal-transduction pathways that control several different proteolytic systems. This level of complexity was unanticipated and poses a variety of challenges to our understanding of how these crucial processes are regulated. Rather than proteolysis being triggered when a single signal is turned from "off" to "on", what is important is the balance between three or more sets of signals with opposing effects. We believe this makes sense from a physiological viewpoint, in that muscle must monitor a variety of physiological variables and enter the state of protein catabolism when "unfavorable" signals are too high or "favorable" signals are too low. However, elucidating the biochemical basis for integration of multiple signals remains a formidable challenge.

Current work in the lab focuses on how muscle homeostasis and protein degradation are regulated by (a) intramuscular calcium and multiple muscle calcium channels; (b) calcium-activated protein kinases; (c) protein phosphatases that modulate signaling. These efforts are greatly facilitated by our unique collection of over 350 mutant strains with altered signaling. In addition, we have two collaborative programs:

a) With N. Szewczyk (Univ. of Nottingham, UK), we are studying the roles of about 1000 genes in maintaining muscle homeostasis. The target genes include the entire genomic set of protein kinases and protein phosphatases, plus a set of genes where mutation produces known phenotypes in muscle.

b) With J. Faeder (Dept. of Computational and Systems Biology) we are undertaking quantitative mathematical modeling of the intricate network that regulates autophagy in muscle, including feedback loops.

The lab environment: The lab has long been known as "The Zoo" for its informal atmosphere and traditional dedication to Marxism (Groucho, not Karl). We are usually a diverse and age-heterogeneous group, ranging from beginning undergraduates to postdocs.

Lehmann, S., Shephard, F., Jacobson, L.A., &amp

Lehmann, S., Shephard, F., Jacobson, L.A., & Szewczyk, N.J.  (2012) Using multiple phenotype assays and epistasis testing to enhance the reliability of RNAi screening and identify regulators of muscle protein degradation in C. elegans. Genes 3:686-701

Lehmann, S., Shephard, F., Jacobson, L.

Lehmann, S., Shephard, F., Jacobson, L.A. & Szewczyk, N.J. (2012) Integrated control of protein degradation in C. elegans muscle. Worm 1(4):141-150

Etheridge T , Oczypok EA , Lehmann S , Fields B

Etheridge T , Oczypok EA , Lehmann S , Fields BD , Shephard F , Jacobson, L.A., Szewczyk, N.J.(2012) Calpains mediate integrin attachment complex maintenance of adult Muscle in Caenorhabditis elegans. PLoS Genet 8: e1002471. doi:10.1371/journal.pgen.1002471

Shephard, F., Adenle, A.A., Jacobson, L.A., and Szewczyk, N.J. (2011) Identification and functional

Shephard, F., Adenle, A.A., Jacobson, L.A., and Szewczyk, N.J. (2011) Identification and functional clustering of genes regulating muscle protein degradation from amongst the known C. elegans muscle mutants. PLoS One 6(9): e24686. doi:10.1371 journal.pone.0024686

Jen-Jacobson, L., and L.A. Jacobson (2008) The role of water and the effects of small ions in sit

Jen-Jacobson, L., and L.A. Jacobson (2008) The role of water and the effects of small ions in site-specific protein-DNA interactions. Pp in Structural Biology of Protein-Nucleic Acid Interactions (Rice, P.A., and C. Correll, eds), Royal Society of Chemistry Publishing:Cambridge, UK.

Szewczyk, N.J., B.K. Peterson, S.J. Barmada, L.P. Parkinson, and L.A. Jacobson (2007) Opposed gro

Szewczyk, N.J., B.K. Peterson, S.J. Barmada, L.P. Parkinson, and L.A. Jacobson (2007) Opposed growth factor signals control protein degradation in muscles of Caenorhabditis elegans. EMBO J 26:935-943

Szewczyk, N.J., I.A. Udranszky, E. Kozak, J. Sunga, S.K. Kim, L.A. Jacobson, and C.A. Conley (200

Szewczyk, N.J., I.A. Udranszky, E. Kozak, J. Sunga, S.K. Kim, L.A. Jacobson, and C.A. Conley (2006) Delayed development and lifespan extension as features of metabolic lifestyle alteration in C. elegans under dietary restriction. J. Exp. Biol. 209:4129-4139

Szewczyk, N.J., and L.A. Jacobson (2005) Signal-transduction networks and the regulation of muscl

Szewczyk, N.J., and L.A. Jacobson (2005) Signal-transduction networks and the regulation of muscle protein degradation. Int. J. Biochem. Cell Biol. 37:1997-2011

Szewczyk, N.J., and L.A. Jacobson (2003) Activated EGL-15 FGF receptor promotes protein degradat

Szewczyk, N.J., and L.A. Jacobson (2003) Activated EGL-15 FGF receptor promotes protein degradation in muscles of Caenorhabditis elegans. EMBO J. 22:5058-5067

Fostel, J.L., L.A. Coste, and L..A. Jacobson (2003) Degradation of transgene-coded and endogenous

Fostel, J.L., L.A. Coste, and L..A. Jacobson (2003) Degradation of transgene-coded and endogenous proteins in the muscles of Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 312:173-177

Szewczyk, N.J., B.K. Peterson, and L.A. Jacobson (2002) Activation of Ras and the MAP kinase path

Szewczyk, N.J., B.K. Peterson, and L.A. Jacobson (2002) Activation of Ras and the MAP kinase pathway promotes protein degradation in muscle cells of Caenorhabditis elegans. Mol. Cell. Biol. 22:4181-4188

Jen-Jacobson, L., L. Engler, and L.A. Jacobson (2000) Structural and thermodynamic strategies for

Jen-Jacobson, L., L. Engler, and L.A. Jacobson (2000) Structural and thermodynamic strategies for site-specific DNA binding proteins. Structure Fold Des. 8:1015-1023

Szewczyk, N.J., J.J. Hartman, S.J. Barmada, and L.A. Jacobson (2000) Genetic defects in acetylcho

Szewczyk, N.J., J.J. Hartman, S.J. Barmada, and L.A. Jacobson (2000) Genetic defects in acetylcholine signalling promote protein degradation in muscle cells of Caenorhabditis elegans. J. Cell Sci. 133:2003-2010
Dr. Jacobson received his Ph.D. (Biochemistry) in 1967 from the University of Illinois and joined the Department in 1967.