Daniel Kirchhofer

Principal Scientist, Early Discovery Biochemistry

POSTDOC MENTOR

• 16
  years at Genentech
• 26
  publications (2010-12)
• 2
  awards & honors

My first project after joining Genentech in 1997 was on blood coagulation proteases, specifically on antibody-based and small molecule inhibitors of tissue factor and factor VIIa. I have worked on proteases and pseudo-proteases (hepatocyte growth factor) ever since.

In the course of many different projects, my wonderful collaborators at Genentech, together with my lab, have explored the structures, functions and biological pathways of proteases implicated in cardiovascular diseases, cancer and psoriasis.

• My Focus

  We are currently investigating proteases that are implicated in lipid metabolism, eye disease and asthma. As potential new therapeutic approaches, we are trying to identify specific antibodies that are able to neutralize protease activities.

  In a complementary project we are exploring the structural and mechanistic basis on how antibodies can regulate the catalytic activity of disease-associated proteases.

• Publications

  • PAR-1 contributes to the innate immune response during viral infection

    Journal of Clinical Investigation, 2013, ISSN: 0021-9738

    Antoniak, Silvio; Owens III, A. Phillip; Baunacke, Martin; Williams, Julie C.; Lee, Rebecca D.; Weithäuser, Alice; Sheridan, Patricia A.; Malz, Ronny; Luyendyk, James P.; Esserman, Denise A.; Trejo, Jo Ann; Kirchhofer, Daniel; Blaxall, Burns C.; Pawlinski, Rafal; Beck, Melinda A.; Rauch, Ursula; Mackman, Nigel

     View on PubMed

  • Mutational tail loss is an evolutionary mechanism for liberating marapsins and other type i serine proteases Fromtransmembrane anchors

    Journal of Biological Chemistry, 2013, ISSN: 0021-9258

    Raman, Kavita; Trivedi, Neil N.; Raymond, Wilfred W.; Ganesan, Rajkumar; Kirchhofer, Daniel; Verghese, George M.; Craik, Charles S.; Schneider, Eric L.; Nimishakavi, Shilpa; Caughey, George H.

     View on PubMed

  • Furin-cleaved PCSK9 is active and modulates LDL receptor and serum cholesterol levels

    Journal of Biological Chemistry, 2012, ISSN: 0021-9258

    Lipari, Michael T; Li, Wei; Moran, Paul; Kong-Beltran, Monica; Sai, Tao; Lai, Joyce; Lin, S Jack; Kolumam, Ganesh; Zavala-Solorio, Jose; Izrael-Tomasevic, Anita; Arnott, David; Wang, Jianyong; Peterson, Andrew S; Kirchhofer, Daniel

     View on PubMed

  • Calcium-independent inhibition of PCSK9 by affinity-improved variants of the LDL receptor EGF(A) domain

    Journal of Molecular Biology, 2012, ISSN: 0022-2836

    Zhang, Yingnan; Zhou, Lijuan; Kong-Beltran, Monica; Li, Wei; Moran, Paul; Wang, Jianyong; Quan, Clifford; Tom, Jeffrey; Kolumam, Ganesh; Elliott, J. Michael; Skelton, Nicholas J.; Peterson, Andrew S.; Kirchhofer, Daniel

     View on PubMed

  • Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease

    Blood, 2012, ISSN: 0006-4971

    Chantrathammachart, Pichika; Mackman, Nigel; Sparkenbaugh, Erica; Wang, Jian-Guo; Parise, Leslie V.; Kirchhofer, Daniel; Key, Nigel S.; Pawlinski, Rafal

     View on PubMed

  • Structural and Functional Analysis of HtrA1 and Its Subdomains

    Structure, 2012, ISSN: 0969-2126

    Eigenbrot, Charles; Ultsch, Mark; Lipari, Michael T.; Moran, Paul; Lin, S. Jack; Ganesan, Rajkumar; Quan, Clifford; Tom, Jeffrey; Sandoval, Wendy; Campagne, Menno van Lookeren; Kirchhofer, Daniel

     View on PubMed

  • Protease activity of MALT1: A mystery unravelled

    Biochemical Journal, 2012, ISSN: 0264-6021

    Kirchhofer, Daniel; Vucic, Domagoj

     View on PubMed

  • Inhibiting alternative pathway complement activation by targeting the factor D exosite

    Journal of Biological Chemistry, 2012, ISSN: 0021-9258

    Katschke Jr, Kenneth J; Wu, Ping; Ganesan, Rajkumar; Kelley, Robert F; Mathieu, Mary A; Hass, Philip E; Murray, Jeremy; Kirchhofer, Daniel; Wiesmann, Christian; Campagne, Menno van Lookeren;

     View on PubMed

  • An allosteric anti-hepsin antibody derived from a constrained phage display library

    PEDS, 2012, ISSN: 1741-0126

    Ganesan, Rajkumar; Zhang, Yingnan; Landgraf, Kyle E; Lin, S.Jack; Moran, Paul; Kirchhofer, Daniel

     View on PubMed

  • Monocyte tissue factor - Dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

    Journal of Clinical Investigation, 2012, ISSN: 0021-9738

    Owens III, A. Phillip; Antoniak, Silvio; Williams, Julie C.; Wang, Jianguo; Mackman, Nigel; Passam, Freda H.; Furie, Barbara C.; Furie, Bruce; Marshall, Stephanie M.; McDaniel, Allison L.; Rudel, Lawrence; Temel, Ryan E.; Hubbard, Brian K.; Johns, Douglas G.; Dutton, Julie-Ann; Moriarty, Patrick M.; Tobias, Peter S.; Curtiss, Linda K.; Daugherty, Alan; Kirchhofer, Daniel; Luyendyk, James P.; Nagarajan, Shanmugam

     View on PubMed

  • Proteolytic activation of pro-macrophage-stimulating protein by hepsin

    Molecular Cancer Research, 29 Aug 2011, ISSN: 1557-3125.

    Ganesan, Rajkumar; Kolumam, Ganesh A; Lin, S Jack; Xie, Ming Hong; Santell, Lydia; Wu, Thomas D; Lazarus, Robert A; Chaudhuri, Amitabha; Kirchhofer, Daniel

     View on PubMed

  • Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S.

    Blood, 2011, ISSN: 0006-4971

    Gavins, F.N.E.; Russell, J.; Senchenkova, E.L.; Paula, L.D.A.; Damazo, A.S.; Esmon, C.T.; Kirchhofer, D.; Hebbel, R.P.; Granger, D.N.

  • Laminin-332 Cleavage by Matriptase Alters Motility Parameters of Prostate Cancer Cells.

    Prostate, 2011, ISSN: 0270-4137

    Tripathi, M.; Potdar, A.A.; Yamashita, H.; Weidow, B.; Cummings, P.T.; Kirchhofer, D.; Quaranta, V.

  • Allosteric Peptide Activators of Pro-Hepatocyte Growth Factor Stimulate Met Signaling.

    The Journal of Biological Chemistry, 2010, ISSN: 0021-9258

    Landgraf, K.E.; Santell, L.; Billeci, K.L.; Quan, C.; Young, J.C.; Maun, H.R.; Kirchhofer, D.; Lazarus, R.A.

  • Proteolysis-induced N-terminal Ectodomain Shedding of the Integral Membrane Glycoprotein CUB Domain-containing Protein 1 (CDCP1) Is Accompanied by Tyrosine Phosphorylation of Its C-terminal Domain and Recruitment of Src and PKCδ.

    Journal of Biological Chemistry, 2010, ISSN: 0021-9258

    He, Y.; Wortmann, A.; Burke, L.; Reid, J.; Adams, M.; Abdul-Jabbar, I.; Quigley, J.; Leduc, R.; Kirchhofer, D.; Hooper, J.

  • Structural and mechanistic insight into how antibodies inhibit serine proteases.

    The Biochemical journal, 2010, ISSN: 1470-8728

    Ganesan, R.; Eigenbrot, C.; Kirchhofer, D.

  • Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer.

    Biological Chemistry, 2010, ISSN: 1437-4315

    Maun, H.; Kirchhofer, D.; Lazarus, R.

  • Hepatocyte growth factor activator (HGFA): molecular structure and interactions with HGFA inhibitor-1 (HAI-1).

    FEBS Journal, 2010, ISSN: 1742-4658

    Eigenbrot, C.; Ganesan, R.; Kirchhofer, D.

  • Role of Coagulation Factors in Cerebral Venous Sinus and Cerebral Microvascular Thrombosis.

    Neurosurgery, 2010, ISSN: 0148-396X

    Nagai, M.; Yilmaz, C.E.; Kirchhofer, D.; Esmon, C.T.; Mackman, N.; Granger, D.N.

  • Local Protease Signaling Contributes to Neural Tube Closure in the Mouse Embryo.

    Developmental Cell, 2010, ISSN: 1534-5807

    Camerer, E.; Barker, A.; Duong, D.N.; Ganesan, R.; Kataoka, H.; Cornelissen, I.; Darragh, M.R.; Hussain, A.; Zheng, Y.W.; Srinivasan, Y.; Brown, C.; Xu, S.M.; Regard, J.B.; Lin, C.Y.; Craik, C.S.; Kirchhofer, D.; Coughlin, S.R.

  • Unraveling the allosteric mechanism of serine protease inhibition by an antibody.

    Structure, 2009, ISSN: 1878-4186

    Ganesan, R.; Eigenbrot, C.; Wu, Y.; Liang, W.C.; Shia, S.; Lipari, M.T.; Kirchhofer, D.

  • Pegylated kunitz domain inhibitor suppresses hepsin-mediated invasive tumor growth and metastasis.

    Cancer Research, 2009, ISSN: 1538-7445

    Li, W.; Wang, B.E.; Moran, P.; Lipari, T.; Ganesan, R.; Corpuz, R.; Ludlam, M.J.; Gogineni, A.; Koeppen, H.; Bunting, S.; Gao, W.Q.; Kirchhofer, D.

  • Levels of microparticle tissue factor activity correlate with coagulation activation in endotoxemic mice

    Journal of Thrombosis and Haemostasis, 2009, ISSN:

    Wang, J.-G.; Manly, D.; Kirchhofer, D.; Pawlinski, R.; Mackman, N.

  • Tissue factor-dependent coagulation contributes to α-naphthylisothiocyanate-induced cholestatic liver injury in mice.

    American Journal of Physiology - Gastrointestinal & Liver Physiology, 2009, ISSN: 0193-1857

    Luyendyk, J.P.; Cantor, G.H.; Kirchhofer, D.; Mackman, N.; Copple, B.L.; Wang, R.P.

  • The serine protease marapsin is expressed in stratified squamous epithelia and is up-regulated in the hyperproliferative epidermis of psoriasis and regenerating wounds.

    Journal of Biological Chemistry, 2009, ISSN: 0021-9258

    Li, W.; Danilenko, D.M.; Bunting, S.; Ganesan, R.; Sa, S.; Ferrando, R.; Wu, T.D.; Kolumam, G.A.; Ouyang, W.; Kirchhofer, D.

  • Noncompetitive inhibition of hepatocyte growth factor-dependent Met signaling by a phage-derived peptide

    Journal of Molecular Biology, 2009, ISSN: 0022-2836

    Tam, E.M.; Runyon, S.T.; Santell, L.; Quan, C.; Yao, X.; Kirchhofer, D.; Skelton, N.J.; Lazarus, R.A.

• Education
  • Swiss Federal Institute of Technology (ETH), Zürich, Switzerland, Ph.D. – 1987
  • La Jolla Cancer Research Foundation, Postdoctoral Fellow – 1987-1990
  • University of Zürich, Zürich, Switzerland, Diploma – 1983
• Awards & Honors
  • Postdoctoral Fellowship grant award from Janggen-Poehn Foundation, Switzerland – 1988
  • Medal for outstanding doctoral thesis by the Swiss Federal Institute of Technology (ETH), Switzerlan – 1987