Patrick Hogan (biologist)

Short description: Cellular & Molecular Biologist

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]

## References

1. ↑ "Hogan Lab" (in en-US). https://www.lji.org/labs/hogan/.
2. ↑ Fiona (2021-04-08). "Company History | CalciMedica" (in en-US). https://calcimedica.com/company-history/.
3. ↑ McCaffrey, P. G.; Luo, C.; Kerppola, T. K.; Jain, J.; Badalian, T. M.; Ho, A. M.; Burgeon, E.; Lane, W. S. et al. (1993-10-29). "Isolation of the cyclosporin-sensitive T cell transcription factor NFATp". Science 262 (5134): 750–754. doi:10.1126/science.8235597. ISSN 0036-8075. PMID 8235597. Bibcode: 1993Sci...262..750M. https://pubmed.ncbi.nlm.nih.gov/8235597.
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. doi:10.1038/32100. ISSN 0028-0836. PMID 9510247. Bibcode: 1998Natur.392...42C. https://pubmed.ncbi.nlm.nih.gov/9510247.
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. doi:10.1101/gad.1102703. ISSN 0890-9369. PMID 12975316. https://pubmed.ncbi.nlm.nih.gov/12975316.
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. doi:10.1126/science.285.5436.2129. ISSN 0036-8075. PMID 10497131. https://pubmed.ncbi.nlm.nih.gov/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. doi:10.1016/j.tcb.2010.09.011. ISSN 0962-8924. PMID 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. doi:10.1038/nature05122. ISSN 1476-4687. PMID 16921383. Bibcode: 2006Natur.443..230P. https://pubmed.ncbi.nlm.nih.gov/16921383.
9. ↑ Zhou, Yubin; Meraner, Paul; Kwon, Hyoung T; Machnes, Danya; Oh-hora, Masatsugu; Zimmer, Jochen; Huang, Yun; Stura, Antonio et al. (2010). "STIM1 gates the store-operated calcium channel ORAI1 in vitro". Nature Structural & Molecular Biology 17 (1): 112–116. doi:10.1038/nsmb.1724. ISSN 1545-9993. PMID 20037597.
10. ↑ Zhou, Yubin; Srinivasan, Prasanna; Razavi, Shiva; Seymour, Sam; Meraner, Paul; Gudlur, Aparna; Stathopulos, Peter B; Ikura, Mitsuhiko et al. (2013). "Initial activation of STIM1, the regulator of store-operated calcium entry". Nature Structural & Molecular Biology 20 (8): 973–981. doi:10.1038/nsmb.2625. ISSN 1545-9993. PMID 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. doi:10.1146/annurev.immunol.021908.132550. ISSN 0732-0582. PMID 20307213.
12. ↑ Sharma, Sonia; Quintana, Ariel; Findlay, Gregory M; Mettlen, Marcel; Baust, Beate; Jain, Mohit; Nilsson, Roland; Rao, Anjana et al. (2013-07-11). "An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry". Nature 499 (7457): 238–242. doi:10.1038/nature12229. ISSN 0028-0836. PMID 23792561. Bibcode: 2013Natur.499..238S.
13. ↑ Quintana, Ariel; Rajanikanth, Vangipurapu; Farber-Katz, Suzette; Gudlur, Aparna; Zhang, Chen; Jing, Ji; Zhou, Yubin; Rao, Anjana et al. (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. doi:10.1073/pnas.1521924112. ISSN 0027-8424. PMID 26644574. Bibcode: 2015PNAS..112E7083Q.
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. doi:10.1038/s41598-019-46862-w. ISSN 2045-2322. PMID 31346209. Bibcode: 2019NatSR...910839K.
15. ↑ Blank, Christian U.; Haining, W. Nicholas; Held, Werner; Hogan, Patrick G.; Kallies, Axel; Lugli, Enrico; Lynn, Rachel C.; Philip, Mary et al. (2019). "Defining 'T cell exhaustion'". Nature Reviews. Immunology 19 (11): 665–674. doi:10.1038/s41577-019-0221-9. ISSN 1474-1741. PMID 31570879.
16. ↑ Martinez, Gustavo J.; Pereira, Renata M.; Äijö, Tarmo; Kim, Edward Y.; Marangoni, Francesco; Pipkin, Matthew E.; Togher, Susan; Heissmeyer, Vigo et al. (2015-02-17). "The transcription factor NFAT promotes exhaustion of activated CD8+ T cells". Immunity 42 (2): 265–278. doi:10.1016/j.immuni.2015.01.006. ISSN 1074-7613. PMID 25680272.
17. ↑ Mognol, Giuliana P.; Spreafico, Roberto; Wong, Victor; Scott-Browne, James P.; Togher, Susan; Hoffmann, Alexander; Hogan, Patrick G.; Rao, Anjana et al. (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. doi:10.1073/pnas.1620498114. ISSN 1091-6490. PMID 28283662.
18. ↑ Seo, Hyungseok; Chen, Joyce; González-Avalos, Edahí; Samaniego-Castruita, Daniela; Das, Arundhoti; Wang, Yueqiang H.; López-Moyado, Isaac F.; Georges, Romain O. et al. (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. doi:10.1073/pnas.1905675116. ISSN 1091-6490. PMID 31152140.
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. doi:10.1038/s41590-021-00964-8. ISSN 1529-2916. PMID 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. doi:10.1073/pnas.1820604116. ISSN 1091-6490. PMID 31019078.

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