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Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (20 January 2024) | Viewed by 6449

Special Issue Editor

Dr. Alexander Y. Tsygankov

E-Mail Website
Guest Editor
Sol Sherry Thrombosis Research Center, Fels Institute for Cancer Research and Department of Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, 3400 N. Broad Street, Philadelphia, PA 19140, USA
Interests: cell signaling; lymphocytes, platelets; protein kinases, protein phosphatases; TULA/UBASH3/STS phosphatase family; Syk/ZAP-70 kinase family

Special Issue Information

Dear Colleagues,

UBASH3/STS/TULA is a novel protein family consisting of two members, both possessing a unique set of protein domains, including a histidine phosphatase domain. The members of this family, especially UBASH3B/STS-1/TULA-2, exhibit protein tyrosine phosphatase activity, thus dephosphorylating several proteins that are critical for receptor-mediated signaling in various cell types, such as protein tyrosine kinases of the Syk/ZAP-70 family. This protein phosphatase activity and some phosphatase-independent molecular functions underlie the key regulatory role of UBASH3/STS/TULA proteins in multiple biological systems, such as immune responses, including both normal host defense and autoimmunity, platelet-mediated hemostatic and thrombotic responses, cancer, cell differentiation, bone formation, and others.

This Special Issue is designed to collect, under a single roof, publications dedicated to the analysis of the existing data on the structure, functions, and biological role of UBASH3/STS/TULA proteins and to the novel research achievements in this field. Manuscripts focused on the molecular basis of UBASH3/STS/TULA proteins’ effects, including targets of regulatory dephosphorylation in their already known and novel substrates, phosphatase-independent mechanisms, and the individual specificity of the two family members are encouraged. Furthermore, manuscripts advancing our understanding of the entire spectrum of biological functions of this family, ranging apparently from immunity and hemostasis to bone formation and brain activity, and the relative contributions of its members to these functions are sought.

All types of publications addressing these key challenges—research articles, reviews, and short communications—are invited.

Dr. Alexander Y. Tsygankov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • UBASH3A/UBASH3B/TULA/TULA-1/TULA-2/STS-1/STS-2
  • signaling
  • kinase
  • phosphatase
  • protein structure
  • enzymatic activity
  • immunity
  • host defense
  • autoimmunity
  • lymphocyte
  • platelet
  • macrophage
  • osteoclast
  • bone
  • cancer

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

5 pages, 184 KiB  
Editorial
Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges
by Alexander Y. Tsygankov
Int. J. Mol. Sci. 2024, 25(8), 4434; https://doi.org/10.3390/ijms25084434 - 18 Apr 2024
Viewed by 451
Abstract
This Special Issue entitled “Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges” is focused on a relatively novel vertebrate gene/protein family termed alternatively TULA, UBASH3, or STS [...] Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)

Research

Jump to: Editorial, Review

11 pages, 1763 KiB  
Communication
UBASH3A Interacts with PTPN22 to Regulate IL2 Expression and Risk for Type 1 Diabetes
by Jeremy R. B. Newman, Patrick Concannon and Yan Ge
Int. J. Mol. Sci. 2023, 24(10), 8671; https://doi.org/10.3390/ijms24108671 - 12 May 2023
Cited by 1 | Viewed by 1157
Abstract
UBASH3A is a negative regulator of T cell activation and IL-2 production and plays key roles in autoimmunity. Although previous studies revealed the individual effects of UBASH3A on risk for type 1 diabetes (T1D; a common autoimmune disease), the relationship of UBASH3A with [...] Read more.
UBASH3A is a negative regulator of T cell activation and IL-2 production and plays key roles in autoimmunity. Although previous studies revealed the individual effects of UBASH3A on risk for type 1 diabetes (T1D; a common autoimmune disease), the relationship of UBASH3A with other T1D risk factors remains largely unknown. Given that another well-known T1D risk factor, PTPN22, also inhibits T cell activation and IL-2 production, we investigated the relationship between UBASH3A and PTPN22. We found that UBASH3A, via its Src homology 3 (SH3) domain, physically interacts with PTPN22 in T cells, and that this interaction is not altered by the T1D risk coding variant rs2476601 in PTPN22. Furthermore, our analysis of RNA-seq data from T1D cases showed that the amounts of UBASH3A and PTPN22 transcripts exert a cooperative effect on IL2 expression in human primary CD8+ T cells. Finally, our genetic association analyses revealed that two independent T1D risk variants, rs11203203 in UBASH3A and rs2476601 in PTPN22, interact statistically, jointly affecting risk for T1D. In summary, our study reveals novel interactions, both biochemical and statistical, between two independent T1D risk loci, and suggests how these interactions may affect T cell function and increase risk for T1D. Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)
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Review

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14 pages, 1765 KiB  
Review
The Ubiquitin-Associated and SH3 Domain-Containing Proteins (UBASH3) Family in Mammalian Development and Immune Response
by Katarina Vukojević, Violeta Šoljić, Vlatka Martinović, Fila Raguž and Natalija Filipović
Int. J. Mol. Sci. 2024, 25(3), 1932; https://doi.org/10.3390/ijms25031932 - 5 Feb 2024
Cited by 1 | Viewed by 871
Abstract
UBASH3A and UBASH3B are protein families of atypical protein tyrosine phosphatases that function as regulators of various cellular processes during mammalian development. As UBASH3A has only mild phosphatase activity, its regulatory effects are based on the phosphatase-independent mechanisms. On the contrary, UBASH3B has [...] Read more.
UBASH3A and UBASH3B are protein families of atypical protein tyrosine phosphatases that function as regulators of various cellular processes during mammalian development. As UBASH3A has only mild phosphatase activity, its regulatory effects are based on the phosphatase-independent mechanisms. On the contrary, UBASH3B has strong phosphatase activity, and the suppression of its receptor signalling is mediated by Syk and Zap-70 kinases. The regulatory functions of UBASH3A and UBASH3B are particularly evident in the lymphoid tissues and kidney development. These tyrosine phosphatases are also known to play key roles in autoimmunity and neoplasms. However, their involvement in mammalian development and its regulatory functions are largely unknown and are discussed in this review. Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)
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12 pages, 426 KiB  
Review
STS-1 and STS-2, Multi-Enzyme Proteins Equipped to Mediate Protein–Protein Interactions
by Barbara Hayes and Peter van der Geer
Int. J. Mol. Sci. 2023, 24(11), 9214; https://doi.org/10.3390/ijms24119214 - 24 May 2023
Cited by 1 | Viewed by 1094
Abstract
STS-1 and STS-2 form a small family of proteins that are involved in the regulation of signal transduction by protein–tyrosine kinases. Both proteins are composed of a UBA domain, an esterase domain, an SH3 domain, and a PGM domain. They use their UBA [...] Read more.
STS-1 and STS-2 form a small family of proteins that are involved in the regulation of signal transduction by protein–tyrosine kinases. Both proteins are composed of a UBA domain, an esterase domain, an SH3 domain, and a PGM domain. They use their UBA and SH3 domains to modify or rearrange protein–protein interactions and their PGM domain to catalyze protein–tyrosine dephosphorylation. In this manuscript, we discuss the various proteins that have been found to interact with STS-1 or STS-2 and describe the experiments used to uncover their interactions. Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)
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24 pages, 2351 KiB  
Review
TULA Proteins in Men, Mice, Hens, and Lice: Welcome to the Family
by Alexander Y. Tsygankov
Int. J. Mol. Sci. 2023, 24(11), 9126; https://doi.org/10.3390/ijms24119126 - 23 May 2023
Cited by 3 | Viewed by 1062
Abstract
The two members of the UBASH3/STS/TULA protein family have been shown to critically regulate key biological functions, including immunity and hemostasis, in mammalian biological systems. Negative regulation of signaling through immune receptor tyrosine-based activation motif (ITAM)- and hemITAM-bearing receptors mediated by Syk-family protein [...] Read more.
The two members of the UBASH3/STS/TULA protein family have been shown to critically regulate key biological functions, including immunity and hemostasis, in mammalian biological systems. Negative regulation of signaling through immune receptor tyrosine-based activation motif (ITAM)- and hemITAM-bearing receptors mediated by Syk-family protein tyrosine kinases appears to be a major molecular mechanism of the down-regulatory effect of TULA-family proteins, which possess protein tyrosine phosphatase (PTP) activity. However, these proteins are likely to carry out some PTP-independent functions as well. Whereas the effects of TULA-family proteins overlap, their characteristics and their individual contributions to cellular regulation also demonstrate clearly distinct features. Protein structure, enzymatic activity, molecular mechanisms of regulation, and biological functions of TULA-family proteins are discussed in this review. In particular, the usefulness of the comparative analysis of TULA proteins in various metazoan taxa, for identifying potential roles of TULA-family proteins outside of their functions already established in mammalian systems, is examined. Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)
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11 pages, 1666 KiB  
Review
The Sts Proteins: Modulators of Host Immunity
by Anika Zaman, Jarrod B. French and Nick Carpino
Int. J. Mol. Sci. 2023, 24(10), 8834; https://doi.org/10.3390/ijms24108834 - 16 May 2023
Cited by 1 | Viewed by 1233
Abstract
The suppressor of TCR signaling (Sts) proteins, Sts-1 and Sts-2, are a pair of closely related signaling molecules that belong to the histidine phosphatase (HP) family of enzymes by virtue of an evolutionarily conserved C-terminal phosphatase domain. HPs derive their name from a [...] Read more.
The suppressor of TCR signaling (Sts) proteins, Sts-1 and Sts-2, are a pair of closely related signaling molecules that belong to the histidine phosphatase (HP) family of enzymes by virtue of an evolutionarily conserved C-terminal phosphatase domain. HPs derive their name from a conserved histidine that is important for catalytic activity and the current evidence indicates that the Sts HP domain plays a critical functional role. Sts-1HP has been shown to possess a readily measurable protein tyrosine phosphatase activity that regulates a number of important tyrosine-kinase-mediated signaling pathways. The in vitro catalytic activity of Sts-2HP is significantly lower than that of Sts-1HP, and its signaling role is less characterized. The highly conserved unique structure of the Sts proteins, in which additional domains, including one that exhibits a novel phosphodiesterase activity, are juxtaposed together with the phosphatase domain, suggesting that Sts-1 and -2 occupy a specialized intracellular signaling niche. To date, the analysis of Sts function has centered predominately around the role of Sts-1 and -2 in regulating host immunity and other responses associated with cells of hematopoietic origin. This includes their negative regulatory role in T cells, platelets, mast cells and other cell types, as well as their less defined roles in regulating host responses to microbial infection. Regarding the latter, the use of a mouse model lacking Sts expression has been used to demonstrate that Sts contributes non-redundantly to the regulation of host immunity toward a fungal pathogen (C. albicans) and a Gram-negative bacterial pathogen (F. tularensis). In particular, Sts-/- animals demonstrate significant resistance to lethal infections of both pathogens, a phenotype that is correlated with some heightened anti-microbial responses of phagocytes derived from mutant mice. Altogether, the past several years have seen steady progress in our understanding of Sts biology. Full article
(This article belongs to the Special Issue Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges)
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