The Herrlich lab is interested in cellular and molecular mechanisms that drive the progression of chronic kidney disease (CKD). Despite recent advances in our therapies, CKD continues to cause great morbidity and mortality, with 15-20% of CKD patients still progressing to dialysis. Our lab aims to identify novel therapeutic approaches that slow or halt CKD progression in patients, using molecular and biochemical approaches as well as mouse genetics to model disease.
We are particularly interested in the role of Angiotensin II (AngII), a blood pressure-regulating hormone that represents a major drug target in hypertension and CKD, and its interconnection with epidermal growth factor (EGF) ligands which regulate many important physiological events in the adult kidney and play a significant role in tubular repair after acute kidney injury. The rate-limiting step in EGF ligand activation is the cell surface cleavage of a pro-form of the hormone by a cell surface metalloprotease. The released ectodomain represents the active ligand that exerts its biological effects by activation of the EGF receptor. AngII is one important stimulus in the kidney for the activation of EGF ligands by metalloprotease cleavage.
Our work currently focuses on two main areas:
(1) A novel Angiotensin II-induced signaling pathway in the kidney that involves metalloprotease (ADAM17) cleavage of the EGF ligand transforming growth factor alpha (TGFalpha) and which has been linked to the progression of CKD in humans, mice and rats. In a large-scale genetic screen (using lentiviral shRNAs), we identified positive and negative regulators of TGFalpha cleavage. We now study these regulators in the context of Angiotensin II-induced signaling in cell lines and in a CKD model in transgenic mice.
(2) Regulatory mechanisms of metalloprotease-cleavage of substrates. Metalloprotease cleavage of cell surface proteins like TGFalpha regulates many critical cellular events and its dysregulation can cause a number of different diseases, depending on the cleaved substrate involved (e.g kidney disease, heart disease, Alzheimer’s disease, cancer). Inhibiting the metalloprotease itself has proven too unspecific (each metalloprotease has many substrates), causes side effects and has failed clinically. A more specific inhibition of the cleavage of a particular disease-involved substrate has been impossible, since it is unknown how cleavage is regulated and whether it is regulated on the metalloprotease level, the substrates level, or both. Recent work from our lab has uncovered significant evidence that cleavage regulation occurs to a substantial degree on the substrate level, opening the possibility of substrate-specific treatments, for example to inhibit TGFalpha cleavage in the kidney. We are using state of the art biological and biochemical techniques, including mass spectrometry, to identify the specific signaling pathways involved.
Herrlich A, Kühn B, Grosse R, Schmid A, Schultz G and Gudermann T. Involvement of Gs and Gi-Proteins in dual coupling of the luteinizing hormone receptor to adenylyl cyclase and phospholipase C. J. Biol. Chem., 271, 16764-16772 (1996). PMID 8663226.
Daub H, Wallasch C, Lankenau A, Herrlich A and Ullrich A. Signal characteristics of G protein-transactivated EGF Receptor. EMBO Journal, 16, 7032-7044 (1997); PMID 9384582.
Herrlich A, Daub H, Knebel A, Herrlich P, Ullrich A, Schultz G,and Gudermann T. Ligand-independent activation of PDGF receptor is a necessary intermediate in LPA-stimulated mitogenic activity in L cells. P.N.A.S., 95, 8985-8990 (1998); PMID 9671791.
Grosse R, Schmid A, Schöneberg T, Herrlich A, Muhn P, Schultz G and Gudermann T. Gonadotropin-releasing hormone (GnRH) receptor initiates multiple signaling pathways by exclusively coupling to Gq/11 proteins. J. Biol. Chem., 275, 9193-9200 (2000); PMID 10734055.
Grosse R, Roelle S, Herrlich A, Höhn J, Gudermann T. Epidermal growth factor receptor kinase mediates Ras activation by gonadotropin- releasing hormone. J. Biol. Chem., 12251-12260 (2000); PMID 10766863.
Herrlich A, Leitch V and King LS. Role of proneuregulin 1 cleavage and human epidermal growth factor receptor activation in hypertonic aquaporin induction. P.N.A.S. 101(44):15799-804 (2004); PMID 15498868.
Herrlich A, Klinman E, Fu J, Sadegh C, Lodish HL. Ectodomain cleavage of the EGF ligands HB-EGF, neuregulin1-beta and TGF-alpha is specifically triggered by different stimuli and involves different PKC isoenzymes. FASEB J, 22 (2008) 22, 4281-4295; PMID 18757500.
Miller MA, Barkal L, Jeng K, Moss M, Herrlich A, Griffith LG, Lauffenburger DA. Proteolytic Activity Matrix Analysis (PrAMA) for Simultaneous Determination of Multiple Protease Activities. Integrative Biology, accepted 11/2010 (2010); PMID 21180771
Dang M, Dubbin K, D’Aiello A, Hartman M, Lodish HL, Herrlich A. EGF ligand release by substrate-specific metalloproteases involves different PKC isoenzymes depending on the stimulus. J. Biol. Chem., first published on March 22, 2011, doi: 10.1074/jbc.M110.187823 (2011); PMID 21454702
Chapter on “Proteases” in Molecular Cell Biology, by Harvey Lodish Arnold Berk, Chris A. Kaiser, and Monty Krieger, 7th edition, 2011, in print.
This page was last modified on 12/1/2011