Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA
Abstract
B and T lymphocyte attenuator (BTLA) is a recently identified inhibitory receptor expressed by B and T cells. We previously identified two tyrosine-containing signaling motifs in the cytoplasmic domain of BTLA that interact with the SHP-1 and SHP-2 phosphatases. BTLA has a third conserved tyrosine-containing motif within the cytoplasmic domain, similar in sequence to a Grb-2 recruitment site. To identify specific interacting proteins that would be recruited to this motif, we carried out an unbiased screen by using synthetic peptides in active (e.g., phosphotyrosil-containing) or control (e.g., non-phosphorylated) forms as baits. Using mass spectrometry, we identified two specific interacting proteins, Grb-2 and the p85 subunit of PI3K. Further, we demonstrate that the interaction with Grb-2 is direct, whereas the recruitment of the p85 subunit by BTLA phosphotyrosile-containing peptides may be indirect via its association with Grb-2. These findings may provide biochemical basis for previously unexplained actions of BTLA.
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BTLA contains a conserved intracellular tyrosine motif suggestive of a Grb-2 recruitment site, which can interact with Grb-2 and the p85 subunit of PI3K in vitro.
“Although it was found that BTLA contains a conserved intracellular tyrosine motif suggestive of a Grb-2 recruitment site, which can interact with Grb-2 and the p85 subunit of PI3K in vitro41”
From BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion (2024) · cites this paper as [41]
Grb2 recruits the p85 subunit of PI3K/Akt, inducing proliferation of B and T lymphocytes.
“Due to adaptor signaling, Grb2 recruits the p85 protein subunit of the PI3K or Akt signaling mechanism, inducing the proliferation of B and T lymphocytes [332].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [332]
BTLA contains ITIM and ITSM motifs and inhibits Grb2 protein in its cytoplasmic domain.
“BTLA contains ITIM and ITSM motifs and stimulates the inhibition of Grb2 protein in its cytoplasmic domain.”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [332]
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“the cytosolic domain of BTLA (27) remains unclear at present.”
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“However, BTLA, which has a long cytoplasmic tail of 111 amino acids can also engage activating signaling pathways via a putative Grb-2 binding motif located upstream of ITIM/ITSM sequences (42) (Figure 2).”
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“(6), who also found a third motif, Grb-2, in the cytoplasmic domain of BTLA that recruits the PI3K-subunit p85, thus, leading to stimulation of the PI3K signaling pathway and subsequent T-cell activation (7).”
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“BTLA, a member of the Ig superfamily, is activated by HVEM binding, attenuating Ag receptor signals through an ITIM/ITSMdependent recruitment of Src homology phosphatase-1 or -2 (33, 34).”
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“It may indicate a physical effect on the synapse andTCRmicroclusters mentioned above, but is also is consistent with the demonstrated binding of Grb2 and Pi3K to a membrane-proximal phosphotyrosine in the intracytoplasmic domain of BTLA, and some prosurvival effects of BTLA (12, 13).”
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“Indeed, BTLA is reported to interact with several proteins, either with activating potential (such as the adaptor proteins Grb2, PI3K, Csk, and Zap70 [24,63]) or with phosphatase activity, such as the protein tyrosine phosphatase receptor type C (PTPRC) [22].”
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“Nonetheless, a third interactor with the intracellular domain of BTLA has been described, Grb-2 (45).”
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“Although the precise molecular targets of BTLA signaling are still obscure (Gavrieli and Murphy, 2006; Wu et al., 2007), BTLA engagement by HVEM can inhibit T cell pro liferation in vitro (Sedy et al., 2005) and promote tolerance induction in vivo (Liu et al., 2009).”
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“However, recent studies by other groups have found that BTLA may also promote cell survival by inducing a gene expression program similar to that induced by ICOS and CD28 costimulation.(8,9) Although BTLA has been characterized as a negative costimulatory molecule on T cells, a number of studies of human CD8C T cells…”
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“While indirect evidence, a peptide containing the conserved phosphorylated Grb-2 recruitment region of the BTLA cytoplasmic domain had the ability to interact with PI3K, suggesting that BTLA may sometimes have a positive, rather than inhibitory, action (8).”
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“This is consistent with the fact that in addition to the ITIM motifs, the BTLA intracellular domain has a conserved membrane-proximal tyrosine containing YDND motif, which binds to growth receptor bound 2 (Grb-2) and interacts with the p85 subunit of phosphatidylinositol 3-kinese (PI3K) [37].”
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“In addition, BTLA has been described to relay its inhibitory signals via GRB2 (Gavrieli & Murphy, 2006).”
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“The cytoplasmic region of BTLA comprises three highly conserved tyrosine-containing motifs; a growth-factor receptor-bound protein 2 (Grb2) binding site, an immunoreceptor tyrosine inhibitory motif (ITIM), and an immunoreceptor tyrosine-based switch motif (ITSM) [6, 17].”
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“BTLA is activated with the binding of HVEM, attenuating Ag receptor signals through an ITIM/ITSM-dependent recruitment of Src homology phosphatase-1 or -2 [11, 12].”
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“Although it was found that BTLA contains a conserved intracellular tyrosine motif suggestive of a Grb-2 recruitment site, whichcaninteract with Grb-2and the p85 subunit ofPI3K invitro 41 , the exact signaling pathway by which BTLA provides co-stimulatory signals is still unclear.”
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“The GRB-2 motif recruits the PI3K protein subunit p85 and further stimulates the PI3K/Akt signaling pathway, which promotes B-and T-cell proliferation [86].”
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Signal Transduction Via Co-stimulatory and Co-inhibitory Receptors
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Pan, M., Zhao, H., Jin, R., Leung, P. S. C., & Shuai, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1156212 · Cited by 23 · see citing works
CD160 and BTLA: LIGHTs out for CD4+ T cells
Kaye, J. G. (2008) · Nature Immunology · doi:10.1038/ni0208-122 · Cited by 23 · see citing works
Predictors of Tumor-Infiltrating Lymphocyte Efficacy in Melanoma
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The Role of B and T Lymphocyte Attenuator in Respiratory System Diseases
Deng, Z. H., Zheng, Y., Cai, P., & Zheng, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.635623 · Cited by 21 · see citing works
“Its extracellular domain is immunoglobulin domain, and intracellular domain contains three conserved motifs: one is the proximal motif which have sequence YDND, an immunoreceptor tyrosine-based inhibitory motif org June 2021 | Volume 12 | Article 6356231 (ITIM), and an immunoreceptor tyrosine-based switch motif (ITSM)…”
BackgroundInfluentialKannan, S., Kurupati, R. K., Doyle, S. A., Freeman, G. J., Schmader, K. E., & Ertl, H. C. J. (2015) · Oncotarget · doi:10.18632/oncotarget.4597 · Cited by 21 · see citing works
“…viewed as a co-inhibitor, one report showed that this may depend on the strength of antigenic stimulation; specifically, in the setting of weak stimulation by alloantigens, BTLA was found to be inhibitory while upon potent alloantigen stimulation BTLA appeared to promote the T cell response [31].”
D’Arrigo, P., Tufano, M., Rea, A., Vigorito, V., Novizio, N., Russo, S., Romano, M. F., & Romano, S. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666181106114421 · Cited by 21 · see citing works
BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression
Mohamed, A. H., Obeid, R. A., Fadhil, A. A., Amir, A. A., Adhab, Z. H., Jabouri, E. A., Ahmad, I. S., & Alshahrani, M. Y. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156412 · Cited by 16 · see citing works
Tumor Cell-Intrinsic BTLA Receptor Inhibits the Proliferation of Tumor Cells via ERK1/2
Cheng, T., Liu, Y., Yan, H., Xi, Y., Duan, L., Wang, Y., Zhang, T., Gu, Y., Wang, X., Wu, C., et al. (2022) · Cells · doi:10.3390/cells11244021 · Cited by 14 · see citing works
“BTLA ligation by HVEM acts in a multifaceted role with the singular ability to control cell growth and the production of interleukin 2 (IL-2) in CD8+ T cells [15], which regulates several downstream signaling pathways including PI3K/AKT, NF-κB, and ERK1/2 in T cells or B cells [15,16,24,38].”
BackgroundPD-1, BTLA and TIGIT as therapeutic targets for rheumatic disease
Kuchroo, J. R., Goldman, N., & Sharpe, A. H. (2025) · Nature Reviews Rheumatology · doi:10.1038/s41584-025-01296-9 · Cited by 9 · see citing works
“In addition, these dysfunctional T reg cells are enriched for components of the PI3K–AKT and mTOR pathways 113 .”
InfluentialInborn errors of immunity associated with defects of self‐tolerance checkpoints: The CD28 family
Rush‐Kittle, J., Gámez-Díaz, L. Y., & Grimbacher, B. (2022) · Pediatric Allergy and Immunology · doi:10.1111/pai.13886 · Cited by 7 · see citing works
The Canonical and Unconventional Ligands of the Herpesvirus Entry Mediator
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Targeting B and T lymphocyte attenuator in cancer immunotherapy
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Experimental advances in understanding allergic airway inflammation
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Immunotherapy as an emerging and promising tool against viral infections
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Clinical significance of BTLA gene expression and rs1982809 polymorphism in pan-cancer
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“[6,19,20] The tyrosine-containing motif of sequence YDND interacts with growth factor receptor binding 2 before engaging with the p85 subunit of PI3K, which is associated with BTLA's pro-survival effect.”
Jin, C.-Y., Su, N., Hu, C., Shao, T., Ji, J., Qin, L.-L., Fan, D., Lin, A., Xiang, L., & Shao, J.-Z. (2021) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2021.104312 · Cited by 2 · see citing works
CD28 Superfamily Costimulatory Molecules in Chronic Pain: Focus on Immunomodulation
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Kuchenreuther, I., Clausen, F.-N., Mazurie, J., Paul, S., Czubayko, F., Mittelstädt, A., Koch, A., Karabiber, A., Hansen, F. J., Arnold, L.-S., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26072875 · Cited by 1 · see citing works
“In some cases, when stimulated by HVEM, it also delivers a pro-survival signal to the T-cell via a specific domain containing a GRB2 recognition motif [20].”
MURPHY, K. M. M., & Gillanders, W. E. (2011) · doi:10.21236/ada545725
Self-citationEnhancement of tolerogenic or immunostimulatory potential of dendritic cells for therapeutic goals
Hanif, J. K. (2011) · doi:10.32657/10356/47574
“The first clue, which suggests BTLA might have inhibitory effects comes from the fact that its cytoplasmic domain has three highly conserved tyrosin motifs, of which two of them are the same a tyrosine motifs of ITIMs [143, 144] which are involved in inhibitory function of PD-1 and CTLA4 [117].”
BackgroundKostimulatorische und -inhibitorische Signale für T-Zellen
Rush‐Kittle, J., & Gámez-Díaz, L. Y. (2021) · Trillium Immunologie · doi:10.47184/ti.2021.01.01
Modélisation de la demande téléphoniquePreprint
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Kosmaczewska, A., Ciszak, L., Andrzejczak, A., Tomkiewicz, A., Partyka, A., Rojek-Gajda, Z., Frydecka, I., Wołowiec, D., Wróbel, T., Bojarska-Junak, A. A., et al. (2025) · Biomolecules · doi:10.3390/biom15111499
“This interaction also points to a potential pro-survival role of BTLA [35].”
THEMIS: new insights into its evolution, structure, and function
Dutta, A., Aravind, L., Choi, S. J., Lesourne, R., & Love, P. E. (2026) · Trends in Immunology · doi:10.1016/j.it.2026.02.006
Immune Checkpoint Molecules: Structure, Function, and Expression
Tayebi, L., & Abdolmaleki, M. (2026) · Springer eBooks · doi:10.1007/978-981-95-8026-2_2
Liu, M., Duan, G., Lai, X., Lin, B., Li, X., Yang, J., Cao, S., Chen, H., Wang, T., Chen, B., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1940260
“However, BTLA ’ s Grb2 motif can recruit the Grb2-PI3K complex, activating the PI3K/Akt pathway under certain conditions, contributing to immune activation (66).”
- Authors
- Gavrieli, M., & Murphy, K. M.
- Affiliations
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Murphy, Kenneth M.
- ORCID
- Murphy, Kenneth M.
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 345
- Issue
- 4
- Pages
- 1440-1445
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2079068721
- Cited by
- 85
- References
- 26
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 1 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P50HL56419)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- BTLA, Grb2, PI3K p85, inhibitory receptors, T and B lymphocytes, protein-protein interaction, SHP-1, SHP2, cytoplasmic domain
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Glutathione Transferase, Humans, Molecular Sequence Data, Oligopeptides, Phosphorylation, Protein Binding, Receptors, Immunologic, Recombinant Fusion Proteins, Blotting, Western, Sequence Homology, Amino Acid, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Protein Subunits, Cell Line, Tumor, Immunoprecipitation, Mice, GRB2 Adaptor Protein
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