University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Clifford A. Lowell, MD, PhD

Clifford A. Lowell, MD, PhD

Professor, Department of Laboratory Medicine, UCSF
Distinguished Professorship in Laboratory Medicine, UCSF

Cancer Center Program Memberships

Cancer Immunology

Research Summary

My laboratory studies tyrosine kinase based signal transduction in innate immune cells. Our general approach involves examination of innate immune function in knockout mice lacking various members of the Src-family or Syk family of tyrosine kinases. Many of these studies also involve use of mice lacking these kinases in specific hematopoietic lineages, such as neutrophils, macrophages or DCs, generated through Cre/Lox technology. We have also used this approach to study other tyrosine kinases (Pyk2/Fak) and intracellular signaling molecules (WASp, STIM1) in innate immune cells. Our major findings have illuminated the function of Src-family and Syk kinases in leukocyte integrin signaling—loss of these kinases results in significant defects in inflammatory and host defense functions mediated by integrins. We have found that leukocyte integrin signaling utilizes the same intracellular pathways initiated by classical immunoreceptors (e.g., FcγRs) by co-opting ITAM-containing adapter proteins. We have also demonstrated the important ways these kinases regulate innate immune cells in the setting of autoimmune and inflammatory diseases, using the Lyn kinase-deficient model. Ongoing studies also involve examination of tyrosine phosphatases (mainly SHP-1) in the counter regulation tyrosine kinases, especially in the setting of hematopoietic malignancy, as well as studies of calcium signaling proteins, using mice lacking these genes specifically in myeloid lineage cells.

Education

Stanford University, B.S., 1979, Biology
The Johns Hopkins University School of Medicine, M.D., 1986, Medicine
The Johns Hopkins University School of Medicine, Ph.D., 1986, Biochemistry/Molecular Biology

Honors & Awards

  • 1979
    Phi Beta Kappa, Stanford University
  • 1979-86
    Medical Scientist Training Program Scholarship, The Johns Hopkins University School of Medicine
  • 1986
    Alpha Omega Alpha, The Johns Hopkins University School of Medicine
  • 1990
    Diplomat of American Board of Internal Medicine
  • 1992
    Awardee Howard Hughes Physician Scientist Training Fellowship
  • 1997
    Awardee American Society of Hematology Junior Faculty Scholar Award
  • 2000
    Awardee Stewart Family Trust Scholar Award
  • 2000
    Awardee Leukemia Research Foundation New Investigator Award
  • 2001
    Awardee Leukemia/Lymphoma Society Scholar Award
  • 2003
    UCSF Immunology Program Annual Student-selected Faculty Speaker
  • 2003
    Appointed Associate Director, UCSF M.D.-Ph.D. (MSTP) Program
  • 2005
    Federation of American Societies for Experimental Biology (FASEB) - elected organizer 2007 meeting

Selected Publications

  1. Cleary SJ, Kwaan N, Tian JJ, Calabrese DR, Mallavia B, Magnen M, Greenland JR, Urisman A, Singer JP, Hays SR, Kukreja J, Hay AM, Howie HL, Toy P, Lowell CA, Morrell CN, Zimring JC, Looney MR. Complement activation on endothelium initiates antibody-mediated acute lung injury. J Clin Invest. 2020 Oct 05.
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  2. Grimes D, Johnson R, Pashos M, Cummings C, Kang C, Sampedro GR, Tycksen E, McBride HJ, Sah R, Lowell CA, Clemens RA. ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense. Proc Natl Acad Sci U S A. 2020 Sep 14.
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  3. Liang J, Zhang JJ, Huang HI, Kanayama M, Youssef N, Jin YJ, Reyes EY, Abram CL, Yang S, Lowell CA, Wang D, Shao L, Shinohara ML, Zhang JY, Hammer GE. The Ubiquitin-Modifying Enzyme A20 Terminates C-Type Lectin Receptor Signals and Is a Suppressor of Host Defense against Systemic Fungal Infection. Infect Immun. 2020 Aug 19; 88(9).
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  4. Poh AR, Dwyer AR, Eissmann MF, Chand AL, Baloyan D, Boon L, Murrey MW, Whitehead L, O'Brien M, Lowell CA, Putoczki TL, Pixley FJ, O'Donoghue RJJ, Ernst M. Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice. Cancer Immunol Res. 2020 04; 8(4):428-435.
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  5. Mahiddine K, Blaisdell A, Ma S, Créquer-Grandhomme A, Lowell CA, Erlebacher A. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J Clin Invest. 2020 01 02; 130(1):389-403.
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  6. Rohwedder I, Kurz ARM, Pruenster M, Immler R, Pick R, Eggersmann T, Klapproth S, Johnson JL, Alsina SM, Lowell CA, Mócsai A, Catz SD, Sperandio M. Src family kinase-mediated vesicle trafficking is critical for neutrophil basement membrane penetration. Haematologica. 2020 Jul; 105(7):1845-1856.
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  7. Cappenberg A, Margraf A, Thomas K, Bardel B, McCreedy DA, Van Marck V, Mellmann A, Lowell CA, Zarbock A. L-selectin shedding affects bacterial clearance in the lung: a new regulatory pathway for integrin outside-in signaling. Blood. 2019 10 24; 134(17):1445-1457.
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  8. Ma J, Abram CL, Hu Y, Lowell CA. CARD9 mediates dendritic cell-induced development of Lyn deficiency-associated autoimmune and inflammatory diseases. Sci Signal. 2019 10 08; 12(602).
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  9. Clemens RA, Lowell CA. CRAC channel regulation of innate immune cells in health and disease. Cell Calcium. 2019 03; 78:56-65.
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  10. McCreedy DA, Lee S, Sontag CJ, Weinstein P, Olivas AD, Martinez AF, Fandel TM, Trivedi A, Lowell CA, Rosen SD, Noble-Haeusslein LJ. Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis. eNeuro. 2018 Jul-Aug; 5(4).
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  11. Rubenstein JL, Geng H, Fraser EJ, Formaker P, Chen L, Sharma J, Killea P, Choi K, Ventura J, Kurhanewicz J, Lowell C, Hwang J, Treseler P, Sneed PK, Li J, Wang X, Chen N, Gangoiti J, Munster PN, Damato B. Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv. 2018 07 10; 2(13):1595-1607.
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  12. Herter JM, Margraf A, Volmering S, Correia BE, Bradshaw JM, Bisconte A, Hill RJ, Langrish CL, Lowell CA, Zarbock A. PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen-1 signalling. Br J Pharmacol. 2018 02; 175(3):429-439.
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  13. Rosales C, Lowell CA, Schnoor M, Uribe-Querol E. Neutrophils: Their Role in Innate and Adaptive Immunity 2017. J Immunol Res. 2017; 2017:9748345.
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  14. Zikherman J, Lowell CA. B cell autoimmunity at the extremes. Nat Immunol. 2017 09 19; 18(10):1065-1066.
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  15. Sinha M, Lowell CA. Efficiency and Specificity of Gene Deletion in Lung Epithelial Doxycycline-Inducible Cre Mice. Am J Respir Cell Mol Biol. 2017 08; 57(2):248-257.
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  16. Clemens RA, Chong J, Grimes D, Hu Y, Lowell CA. STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production. Blood. 2017 09 28; 130(13):1565-1577.
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  17. Costa S, Marini O, Bevilacqua D, DeFranco AL, Hou B, Lonardi S, Vermi W, Rodegher P, Panato A, Tagliaro F, Lowell CA, Cassatella MA, Girolomoni G, Scapini P. Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells. J Leukoc Biol. 2017 09; 102(3):791-803.
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  18. Abram CL, Lowell CA. Shp1 function in myeloid cells. J Leukoc Biol. 2017 09; 102(3):657-675.
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  19. Roubinian NH, Looney MR, Keating S, Kor DJ, Lowell CA, Gajic O, Hubmayr R, Gropper M, Koenigsberg M, Wilson GA, A Matthay M, Toy P, Murphy EL. Differentiating pulmonary transfusion reactions using recipient and transfusion factors. Transfusion. 2017 07; 57(7):1684-1690.
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  20. Chen J, Zhong MC, Guo H, Davidson D, Mishel S, Lu Y, Rhee I, Pérez-Quintero LA, Zhang S, Cruz-Munoz ME, Wu N, Vinh DC, Sinha M, Calderon V, Lowell CA, Danska JS, Veillette A. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature. 2017 04 27; 544(7651):493-497.
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