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Cells
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SH2 and SH3 Domains: Cellular Signalling and Diseases
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SH2 and SH3 Domains: Cellular Signalling and Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 12486

Special Issue Editor

Prof. Dr. Laszlo Buday

E-Mail Website
Guest Editor
Institute of Enzymology, Research Center for Natural Sciences, Budapest, Hungary
Interests: cell signaling; tyrosine kinases; scaffold protein; SH2 and SH3 domains; Ras signaling

Special Issue Information

Dear Colleagues, 

SH2 and SH3 domains are small noncatalytic protein modules that are conserved among a series of proteins. They couple growth factor receptors to intracellular signal transduction pathways by mediating protein–protein interactions. While SH2 domains bind tyrosine-phosphorylated polypeptides, SH3 domains interact with ligands that possess short proline-rich motifs. It has been well-established how enzymes such as the Src tyrosine kinase family, phospholipase C-gamma, or STAT proteins are regulated by the assistance of SH2 and SH3 domains. These domains are also present in proteins without any catalytic activity, including adaptor, anchor, docking, or scaffold proteins, which serve to link tyrosine kinases to specific target proteins. Although the basal mechanism of action of SH2 and SH3 domains has been well-known for some time, recent findings have suggested a role of both SH2 and SH3 domains in lipid binding. In addition, direct tyrosine phosphorylation of the SH3 domains has emerged as a novel regulatory mechanism.

In this Special Issue, we will provide an open access platform for reviews and original research papers describing all aspects of research on SH2 and SH3 domains.

Prof. Dr. Laszlo Buday
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • SH2 and SH3 domains
  • Tyrosine kinases
  • Phosphorylation
  • Protein–protein interactions

Published Papers (3 papers)

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Research

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18 pages, 4655 KiB  
Article
Solution NMR Structure of the SH3 Domain of Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and Supports a Role in Lipid Mediator Binding
by Orsolya Tőke, Kitti Koprivanacz, László Radnai, Balázs Merő, Tünde Juhász, Károly Liliom and László Buday
Cells 2021, 10(1), 173; https://doi.org/10.3390/cells10010173 - 16 Jan 2021
Cited by 3 | Viewed by 2707
Abstract
SH3 domains constitute an important class of protein modules involved in a variety of cellular functions. They participate in protein-protein interactions via their canonical ligand binding interfaces composed of several evolutionarily conserved aromatic residues forming binding grooves for typical (PxxP) and atypical (PxxxPR, [...] Read more.
SH3 domains constitute an important class of protein modules involved in a variety of cellular functions. They participate in protein-protein interactions via their canonical ligand binding interfaces composed of several evolutionarily conserved aromatic residues forming binding grooves for typical (PxxP) and atypical (PxxxPR, RxxK, RKxxY) binding motifs. The calcium/calmodulin-dependent serine protein kinase (CASK)-interacting protein 1, or Caskin1, a multidomain scaffold protein regulating the cortical actin filaments, is enriched in neural synapses in mammals. Based on its known interaction partners and knock-out animal studies, Caskin1 may play various roles in neural function and it is thought to participate in several pathological processes of the brain. Caskin1 has a single, atypical SH3 domain in which key aromatic residues are missing from the canonical binding groove. No protein interacting partner for this SH3 domain has been identified yet. Nevertheless, we have recently demonstrated the specific binding of this SH3 domain to the signaling lipid mediator lysophospatidic acid (LPA) in vitro. Here we report the solution NMR structure of the human Caskin1 SH3 domain and analyze its structural features in comparison with other SH3 domains exemplifying different strategies in target selectivity. The key differences revealed by our structural study show that the canonical binding groove found in typical SH3 domains accommodating proline-rich motifs is missing in Caskin1 SH3, most likely excluding a bona fide protein target for the domain. The LPA binding site is distinct from the altered protein binding groove. We conclude that the SH3 domain of Caskin1 might mediate the association of Caskin1 with membrane surfaces with locally elevated LPA content. Full article
(This article belongs to the Special Issue SH2 and SH3 Domains: Cellular Signalling and Diseases)
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13 pages, 1853 KiB  
Article
Targeting the Interaction between the SH3 Domain of Grb2 and Gab2
by Francesca Malagrinò, Antonio Coluccia, Marianna Bufano, Giuseppe La Regina, Michela Puxeddu, Angelo Toto, Lorenzo Visconti, Alessio Paone, Maria Chiara Magnifico, Francesca Troilo, Francesca Cutruzzolà, Romano Silvestri and Stefano Gianni
Cells 2020, 9(11), 2435; https://doi.org/10.3390/cells9112435 - 7 Nov 2020
Cited by 6 | Viewed by 2770
Abstract
Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is [...] Read more.
Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is crucial for the activation of the proliferation-signaling pathway Ras/Erk, thus representing a potential pharmacological target. In this study, we identified, by virtual screening, seven potential inhibitor molecules that were experimentally tested through kinetic and equilibrium binding experiments. One compound showed a remarkable effect in lowering the affinity of the C-SH3 domain for Gab2. This inhibitory effect was subsequently validated in cellula by using lung cancer cell lines A549 and H1299. Our results are discussed under the light of previous works on the C-SH3:Gab2 interaction. Full article
(This article belongs to the Special Issue SH2 and SH3 Domains: Cellular Signalling and Diseases)
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Review

Jump to: Research

16 pages, 1490 KiB  
Review
Novel Roles of SH2 and SH3 Domains in Lipid Binding
by Szabolcs Sipeki, Kitti Koprivanacz, Tamás Takács, Anita Kurilla, Loretta László, Virag Vas and László Buday
Cells 2021, 10(5), 1191; https://doi.org/10.3390/cells10051191 - 13 May 2021
Cited by 5 | Viewed by 5919
Abstract
Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the [...] Read more.
Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the recognition of local protein or lipid modifications by modular protein interactions is now a central paradigm in signaling. Such molecular interactions are mediated by specific protein interaction domains. The first such domain identified was the SH2 domain, which was postulated to be a reader capable of finding and binding protein partners displaying phosphorylated tyrosine side chains. The SH3 domain was found to be involved in the formation of stable protein sub-complexes by constitutively attaching to proline-rich surfaces on its binding partners. The SH2 and SH3 domains have thus served as the prototypes for a diverse collection of interaction domains that recognize not only proteins but also lipids, nucleic acids, and small molecules. It has also been found that particular SH2 and SH3 domains themselves might also bind to and rely on lipids to modulate complex assembly. Some lipid-binding properties of SH2 and SH3 domains are reviewed here. Full article
(This article belongs to the Special Issue SH2 and SH3 Domains: Cellular Signalling and Diseases)
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