Patrick Hogan (biologist) explained

Patrick G. Hogan is a cellular and molecular biologist who studies how cellular signaling leads to gene expression. He obtained his bachelor’s degree from Harvard University and a PhD in neurobiology from Harvard Medical School. In 2010, he moved to the La Jolla Institute for Immunology in San Diego as a Professor in the Division of Signaling and Gene Expression.[1] He is a Founder and Member of the Scientific Advisory Board, CalciMedica Inc, La Jolla, CA.[2]

Research

Hogan's research interests have been focused on the signaling and gene expression pathways that result from calcium entry into cells. He molecularly cloned the transcription factor NFAT, which is dephosphorylated by the calcium-regulated phosphatase calcineurin,[3] and solved its structure in collaboration with the laboratory of Stephen Harrison at Harvard Medical School.[4] [5] He investigated the protein-protein interactions between calcineurin and NFAT.[6] [7] Subsequently, he identified ORAI1 as the pore subunit of the store-operated Ca2+ channel in human cells,[8] and investigated the regulation of ORAI1 by STIM1,[9] [10] a single-pass transmembrane protein located in the membrane of the endoplasmic reticulum (ER) that senses the concentration of calcium in the ER stores and then opens the ORAI1 calcium channel in the plasma membrane.[11] He has made major contributions to our understanding of the mechanisms and regulation of cellular calcium signaling, particularly modulation of the STIM-ORAI pathway in the context of ER-plasma membrane junctions, which he has investigated using whole-genome screens, super-resolution microscopy and single-molecule tracking.[12] [13] [14]

T cells that enter a tumor initially attempt to destroy the cancer cells but then enter a state in which they are poorly responsive and fail to attack the tumor cells effectively. This state also occurs during chronic viral infections and has been termed “T cell exhaustion.”[15] Hogan's research showed that T cell exhaustion is driven by the transcription factor NFAT in the absence of its transcriptional partners Fos and Jun.[16] With Fos and Jun, NFAT promotes effective T cell activation and tumor killing, but in their absence, NFAT induces the secondary transcription factors NR4A and TOX, which then cooperate with NFAT to induce the exhausted or hyporesponsive state.[17] [18] He also showed that BATF transcription factors play an important role in preventing the exhaustion of T cells with Chimeric Antigen Receptors (CAR),[19] and that disruption of the NFAT:AP-1 interaction can be achieved with small molecules and may be a promising therapeutic approach.[20]

Notes and References

  1. Web site: Hogan Lab . 2022-04-04 . La Jolla Institute for Immunology . en-US.
  2. Web site: Fiona . 2021-04-08 . Company History CalciMedica . 2022-04-04 . en-US.
  3. McCaffrey . P. G. . Luo . C. . Kerppola . T. K. . Jain . J. . Badalian . T. M. . Ho . A. M. . Burgeon . E. . Lane . W. S. . Lambert . J. N. . Curran . T. . 1993-10-29 . Isolation of the cyclosporin-sensitive T cell transcription factor NFATp . Science . 262 . 5134 . 750–754 . 10.1126/science.8235597 . 0036-8075 . 8235597. 1993Sci...262..750M .
  4. Chen . L. . Glover . J. N. . Hogan . P. G. . Rao . A. . Harrison . S. C. . 1998-03-05 . Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA . Nature . 392 . 6671 . 42–48 . 10.1038/32100 . 0028-0836 . 9510247. 1998Natur.392...42C . 4305535 .
  5. Hogan . Patrick G. . Chen . Lin . Nardone . Julie . Rao . Anjana . 2003-09-15 . Transcriptional regulation by calcium, calcineurin, and NFAT . Genes & Development . 17 . 18 . 2205–2232 . 10.1101/gad.1102703 . 0890-9369 . 12975316. free .
  6. Aramburu . J. . Yaffe . M. B. . López-Rodríguez . C. . Cantley . L. C. . Hogan . P. G. . Rao . A. . 1999-09-24 . Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A . Science . 285 . 5436 . 2129–2133 . 10.1126/science.285.5436.2129 . 0036-8075 . 10497131.
  7. Li . Huiming . Rao . Anjana . Hogan . Patrick G. . 2011 . Interaction of calcineurin with substrates and targeting proteins . Trends in Cell Biology . 21 . 2 . 91–103 . 10.1016/j.tcb.2010.09.011 . 0962-8924 . 3244350 . 21115349.
  8. Prakriya . Murali . Feske . Stefan . Gwack . Yousang . Srikanth . Sonal . Rao . Anjana . Hogan . Patrick G. . 2006-09-14 . Orai1 is an essential pore subunit of the CRAC channel . Nature . 443 . 7108 . 230–233 . 10.1038/nature05122 . 1476-4687 . 16921383. 2006Natur.443..230P . 4310221 .
  9. Zhou . Yubin . Meraner . Paul . Kwon . Hyoung T . Machnes . Danya . Oh-hora . Masatsugu . Zimmer . Jochen . Huang . Yun . Stura . Antonio . Rao . Anjana . Hogan . Patrick G . 2010 . STIM1 gates the store-operated calcium channel ORAI1 in vitro . Nature Structural & Molecular Biology . 17 . 1 . 112–116 . 10.1038/nsmb.1724 . 1545-9993 . 2902271 . 20037597.
  10. Zhou . Yubin . Srinivasan . Prasanna . Razavi . Shiva . Seymour . Sam . Meraner . Paul . Gudlur . Aparna . Stathopulos . Peter B . Ikura . Mitsuhiko . Rao . Anjana . Hogan . Patrick G . 2013 . Initial activation of STIM1, the regulator of store-operated calcium entry . Nature Structural & Molecular Biology . 20 . 8 . 973–981 . 10.1038/nsmb.2625 . 1545-9993 . 3784406 . 23851458.
  11. Hogan . Patrick G. . Lewis . Richard S. . Rao . Anjana . 2010-04-23 . Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI . Annual Review of Immunology . 28 . 491–533 . 10.1146/annurev.immunol.021908.132550 . 0732-0582 . 2861828 . 20307213.
  12. Sharma . Sonia . Quintana . Ariel . Findlay . Gregory M . Mettlen . Marcel . Baust . Beate . Jain . Mohit . Nilsson . Roland . Rao . Anjana . Hogan . Patrick G . 2013-07-11 . An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry . Nature . 499 . 7457 . 238–242 . 10.1038/nature12229 . 0028-0836 . 3846693 . 23792561. 2013Natur.499..238S .
  13. Quintana . Ariel . Rajanikanth . Vangipurapu . Farber-Katz . Suzette . Gudlur . Aparna . Zhang . Chen . Jing . Ji . Zhou . Yubin . Rao . Anjana . Hogan . Patrick G. . 2015-12-22 . TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling . Proceedings of the National Academy of Sciences of the United States of America . 112 . 51 . E7083–E7092 . 10.1073/pnas.1521924112 . 0027-8424 . 4697383 . 26644574. 2015PNAS..112E7083Q . free .
  14. Katz . Zachary B. . Zhang . Chen . Quintana . Ariel . Lillemeier . Björn F. . Hogan . Patrick G. . 2019-07-25 . Septins organize endoplasmic reticulum-plasma membrane junctions for STIM1-ORAI1 calcium signalling . Scientific Reports . 9 . 1 . 10839 . 10.1038/s41598-019-46862-w . 2045-2322 . 6658532 . 31346209. 2019NatSR...910839K .
  15. Blank . Christian U. . Haining . W. Nicholas . Held . Werner . Hogan . Patrick G. . Kallies . Axel . Lugli . Enrico . Lynn . Rachel C. . Philip . Mary . Rao . Anjana . Restifo . Nicholas P. . Schietinger . Andrea . 2019 . Defining 'T cell exhaustion' . Nature Reviews. Immunology . 19 . 11 . 665–674 . 10.1038/s41577-019-0221-9 . 1474-1741 . 7286441 . 31570879.
  16. Martinez . Gustavo J. . Pereira . Renata M. . Äijö . Tarmo . Kim . Edward Y. . Marangoni . Francesco . Pipkin . Matthew E. . Togher . Susan . Heissmeyer . Vigo . Zhang . Yi Chen . Crotty . Shane . Lamperti . Edward D. . 2015-02-17 . The transcription factor NFAT promotes exhaustion of activated CD8+ T cells . Immunity . 42 . 2 . 265–278 . 10.1016/j.immuni.2015.01.006 . 1074-7613 . 4346317 . 25680272.
  17. Mognol . Giuliana P. . Spreafico . Roberto . Wong . Victor . Scott-Browne . James P. . Togher . Susan . Hoffmann . Alexander . Hogan . Patrick G. . Rao . Anjana . Trifari . Sara . 2017-03-28 . Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells . Proceedings of the National Academy of Sciences of the United States of America . 114 . 13 . E2776–E2785 . 10.1073/pnas.1620498114 . 1091-6490 . 5380094 . 28283662. free .
  18. Seo . Hyungseok . Chen . Joyce . González-Avalos . Edahí . Samaniego-Castruita . Daniela . Das . Arundhoti . Wang . Yueqiang H. . López-Moyado . Isaac F. . Georges . Romain O. . Zhang . Wade . Onodera . Atsushi . Wu . Cheng-Jang . 2019-06-18 . TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion . Proceedings of the National Academy of Sciences of the United States of America . 116 . 25 . 12410–12415 . 10.1073/pnas.1905675116 . 1091-6490 . 6589758 . 31152140. free .
  19. Seo . Hyungseok . González-Avalos . Edahí . Zhang . Wade . Ramchandani . Payal . Yang . Chao . Lio . Chan-Wang J. . Rao . Anjana . Hogan . Patrick G. . 2021 . BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells . Nature Immunology . 22 . 8 . 983–995 . 10.1038/s41590-021-00964-8 . 1529-2916 . 8319109 . 34282330.
  20. Mognol . Giuliana P. . González-Avalos . Edahí . Ghosh . Srimoyee . Spreafico . Roberto . Gudlur . Aparna . Rao . Anjana . Damoiseaux . Robert . Hogan . Patrick G. . 2019-05-14 . Targeting the NFAT:AP-1 transcriptional complex on DNA with a small-molecule inhibitor . Proceedings of the National Academy of Sciences of the United States of America . 116 . 20 . 9959–9968 . 10.1073/pnas.1820604116 . 1091-6490 . 6525529 . 31019078. free .

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