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Patrick Hogan (for Wikipedia)

Dr. Patrick G. Hogan, Ph.D. 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].

Dr. 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 Steve 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 Ca 2+ 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]. Dr. 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

Categories: Harvard Medical School alumni Living people

1. https://www.lji.org/labs/hogan/

2. https://calcimedica.com/company-history/

3. McCaffrey PG, Luo C, Kerppola TK, Jain J, Badalian TM, Ho AM, Burgeon E, Lane WS, Lambert JN, Curran

T, Verdine GL, Rao A, Hogan PG (1993) Isolation of the cyclosporin-sensitive T cell transcription factor

NFATp. Science 262, 750-754. PMID 8235597

4. Chen L, Glover JNM, Hogan PG, Rao A, Harrison SC (1998) Structure of the DNA-binding domains of

NFAT, Fos and Jun bound to DNA. Nature 392, 42-48. PMID 9510247

5. Hogan PG, Chen L, Nardone J, Rao A (2003) Transcriptional regulation by calcium, calcineurin, and NFAT:

structural and cell biological aspects. Genes & amp; Development 17, 2205-2232. PMID 12975316

6. Aramburu J, Yaffe MB, Lopez-Rodriguez C, Cantley LC, Hogan PG, Rao A (1999) Affinity-driven peptide

selection of an NFAT inhibitor more selective than cyclosporin A. Science 285, 2129-2133. PMID 10497131

7. Li H, Rao A, Hogan PG (2011) Interaction of calcineurin with substrates and targeting proteins. Trends in

Cell Biology 21, 91-103. PMID 21115349 PMCID 3244350.

8. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of

the CRAC channel. Nature 443, 230-233. PMID 16921383

9. Zhou Y, Meraner P, Kwon HT, Machnes D, Oh-hora M, Zimmer J, Huang Y, Stura A, Rao A, Hogan PG

(2010) STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nature Structural &amp;amp; Molecular Biology

17, 112–116. PMID 20037597 PMCID 2902271

10. Zhou Y, Srinivasan P, Razavi S, Seymour S, Meraner P, Gudlur A, Stathopulos P, Ikura M, Rao A, Hogan

PG (2013) Initial activation of STIM1, the regulator of store-operated calcium entry. Nature Structural &amp;amp;

Molecular Biology 20, 973-981. PMID 23851458 PMCID 3784406

11. Hogan PG, Lewis RL, Rao A (2010) Molecular basis of calcium signalling in lymphocytes: STIM and ORAI.

Annual Review of Immunology 28, 491-533. PMID 20307213 PMCID 2861828

12. Sharma S, Quintana A, Findlay GM, Mettlen M, Baust B, Jain M, Nilsson R, Rao A, Hogan PG (2013) An

siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca 2+ entry. Nature 499,

238-242. PMID 23792561 PMCID 3846693

13. Quintana A, Rajanikanth V, Farber-Katz S, Gudlur A, Zhang C, Jing J, Zhou Y, Rao A, Hogan PG (2015)

TMEM110 regulates the maintenance and remodeling of ER–plasma membrane junctions competent for

STIM–ORAI signaling. Proceedings of the National Academy of Sciences USA 112, E7083-E7092. PMID

26644574 PMCID 4697383

14. Katz ZB, Zhang C, Quintana A, Lillemeier BF, Hogan PG (2019) Septins organize endoplasmic reticulum-

plasma membrane junctions for STIM1-ORAI1 calcium signalling. Scientific Reports, 598, 1695 PMID

31346209 PMCID PMC6658532

15. Blank CU, Haining WN, Helf W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A., Restifo NP,

Schietinger A, Schumacher TN, Schwartzberg PL, Sharpe AH, Speiser DE, Wherry EJ, Youngblood BA, Zehn

D (2019) Defining ‘T cell exhaustion’. Nat Rev Immunol 19, 665-674. PMID 31570879 PMCID PMC7286441

16. Martinez GJ, Pereira RM, Äijö T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang Y-C,

Crotty S, Lamperti ED, Ansel KM, Mempel TR, Lähdesmäki H, Hogan PG, Rao A (2015) The transcription

factor NFAT promotes exhaustion of activated CD8 + T cells. Immunity 42, 265-278. PMID 25680272 PMCID

4346317

17. Mognol GP, Spreafico R, Wong V, Scott-Browne J, Togher S, Hoffmann A, Hogan PG, Rao A, Trifari S

(2017) Exhaustion-associated regulatory regions in CD8 + tumor-infiltrating T cells. Proceedings of the National

Academy of Sciences USA 114, E2776-E2785. PMID 28283662 PMCID 5380094.

18. Seo H, Chen J, González-Avalos E, Samaniego-Castruita D, Das A, Wang YH, López-Moyado IF, Georges

RO, Zhang W, Onodera A, Wu CJ, Lu LF, Hogan PG, Bhandoola A, Rao A (2019) TOX and TOX2

transcription factors cooperate with NR4A transcription factors to impose CD8 + T cell exhaustion. Proc Natl

Acad Sci USA 116, 12410-12415 PMID 31152140 PMCID PMC6589758

19. Seo H, Gonzàlez-Avalos E, Zhang W, Ramchandani P, Lio C-W J, Rao A, Hogan PG (2021) BATF and

IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells. Nature Immunol, 22, 983-995. PMID:

34282330 PMCID: PMC8319109

19. Mognol GP, González-Avalos E, Ghosh S, Spreafico R, Gudlur A, Rao A, Damoiseaux R, Hogan PG

(2019) Targeting the NFAT–AP1 transcriptional complex on DNA with a small-molecule inhibitor. Proceedings

of the National Academy of Sciences USA 116, E9959-9968. PMID 31019078 PMCID 6525529