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Protein and Lipid Kinases: Structure and Function
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Protein and Lipid Kinases: Structure and Function

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 (31 October 2023) | Viewed by 5662

Special Issue Editor

Dr. Doriano Fabbro

E-Mail Website
Guest Editor
Cellestia Biotech, 4057 Basel, Switzerland
Interests: PI3K; mTOR inhibitor; cancer; overgrowth syndrome; mTORopathy; TSC; PROS; apds; PTEN hamartoma; brain penetration

Special Issue Information

Dear Colleagues,

Reversible protein phosphorylation regulates basic cellular processes, such as metabolism, gene expression, cellular proliferation and differentiation, and controls most events in the various stages of the cell cycle, as well as cell responses to environmental and nutritional stresses. Understanding the regulation of protein and lipid kinases (and their corresponding phosphatases) is of outmost importance for the better understanding of signal transduction basics, as well as for the exploitation of this target class for pharmacological intervention.

To obtain a comprehensive understanding of the structure and function of protein and lipid kinases, this Special Issue attempts to assemble various aspects of their regulation, including inhibitors and targeted protein degradation, combined with a variety of novel methodologies, including crystallography and magnetic resonance.

Dr. Doriano Fabbro
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

  • kinase regulated pathways in health and disease
  • NMR
  • Cryo-EM
  • X-ray
  • kinase inhibitors and activators
  • regulation of kinases
 

Published Papers (3 papers)

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Research

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16 pages, 3379 KiB  
Article
The Impact of p70S6 Kinase-Dependent Phosphorylation of Gemin2 in UsnRNP Biogenesis
by Lea Marie Esser, Qiaoping Li, Maximilian Jüdt, Thilo Kähne, Björn Stork, Matthias Grimmler, Sebastian Wesselborg and Christoph Peter
Int. J. Mol. Sci. 2023, 24(21), 15552; https://doi.org/10.3390/ijms242115552 - 25 Oct 2023
Viewed by 973
Abstract
The survival motor neuron (SMN) complex is a multi-megadalton complex involved in post-transcriptional gene expression in eukaryotes via promotion of the biogenesis of uridine-rich small nuclear ribonucleoproteins (UsnRNPs). The functional center of the complex is formed from the SMN/Gemin2 subunit. By binding the [...] Read more.
The survival motor neuron (SMN) complex is a multi-megadalton complex involved in post-transcriptional gene expression in eukaryotes via promotion of the biogenesis of uridine-rich small nuclear ribonucleoproteins (UsnRNPs). The functional center of the complex is formed from the SMN/Gemin2 subunit. By binding the pentameric ring made up of the Sm proteins SmD1/D2/E/F/G and allowing for their transfer to a uridine-rich short nuclear RNA (UsnRNA), the Gemin2 protein in particular is crucial for the selectivity of the Sm core assembly. It is well established that post-translational modifications control UsnRNP biogenesis. In our work presented here, we emphasize the crucial role of Gemin2, showing that the phospho-status of Gemin2 influences the capacity of the SMN complex to condense in Cajal bodies (CBs) in vivo. Additionally, we define Gemin2 as a novel and particular binding partner and phosphorylation substrate of the mTOR pathway kinase ribosomal protein S6 kinase beta-1 (p70S6K). Experiments using size exclusion chromatography further demonstrated that the Gemin2 protein functions as a connecting element between the 6S complex and the SMN complex. As a result, p70S6K knockdown lowered the number of CBs, which in turn inhibited in vivo UsnRNP synthesis. In summary, these findings reveal a unique regulatory mechanism of UsnRNP biogenesis. Full article
(This article belongs to the Special Issue Protein and Lipid Kinases: Structure and Function)
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13 pages, 2392 KiB  
Article
Beta-Secretase 1 Recruits Amyloid-Beta Precursor Protein to ROCK2 Kinase, Resulting in Erroneous Phosphorylation and Beta-Amyloid Plaque Formation
by István Hajdú, Barbara M. Végh, András Szilágyi and Péter Závodszky
Int. J. Mol. Sci. 2023, 24(13), 10416; https://doi.org/10.3390/ijms241310416 - 21 Jun 2023
Viewed by 1000
Abstract
The amyloidogenic processing of APP depends on two events: its phosphorylation by ROCK2 (at Thr654) and the phosphorylation of the APP-cleaving enzyme BACE1 (at Ser498). However, the mechanisms and structural details of APP-ROCK2 and BACE1-ROCK2 binding are unknown. Using direct physical methods in [...] Read more.
The amyloidogenic processing of APP depends on two events: its phosphorylation by ROCK2 (at Thr654) and the phosphorylation of the APP-cleaving enzyme BACE1 (at Ser498). However, the mechanisms and structural details of APP-ROCK2 and BACE1-ROCK2 binding are unknown. Using direct physical methods in combination with an in silico approach, we found that BACE1 binds into the substrate-binding groove of ROCK2 with a low affinity (Kd = 18 µM), while no binding of APP to ROCK2 alone could be detected. On the other hand, a strong association (Kd = 3.5 nM) of APP to the weak ROCK2-BACE1 complex was observed, although no stable ternary complex was detected, i.e., BACE1 was displaced by APP. We constructed a sequential functional model: (1) BACE1 weakly binds to ROCK2 and induces an allosteric conformational change in ROCK2; (2) APP strongly binds to the ROCK2-BACE1 complex, and BACE1 is released; and (3) ROCK2 phosphorylates APP at Thr654 (leading to a longer stay in the early endosome during APP processing). Direct fluorescence titration experiments showed that the APP646–664 or APP665–695 fragments did not bind separately to the ROCK2-BACE1 complex. Based on these observations, we conclude that two binding sites are involved in the ROCK2-APP interaction: (1) the substrate-binding groove, where the APP646–664 sequence containing Thr654 sits and (2) the allosteric binding site, where the APP665–695 sequence binds. These results open the way to attack the allosteric site to prevent APP phosphorylation at Thr654 by ROCK2 without inhibiting the activity of ROCK2 towards its other substrates. Full article
(This article belongs to the Special Issue Protein and Lipid Kinases: Structure and Function)
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Review

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22 pages, 2464 KiB  
Review
MKK4 Inhibitors—Recent Development Status and Therapeutic Potential
by Leon Katzengruber, Pascal Sander and Stefan Laufer
Int. J. Mol. Sci. 2023, 24(8), 7495; https://doi.org/10.3390/ijms24087495 - 19 Apr 2023
Cited by 2 | Viewed by 3179
Abstract
MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, [...] Read more.
MKK4 (mitogen-activated protein kinase kinase 4; also referred to as MEK4) is a dual-specificity protein kinase that phosphorylates and regulates both JNK (c-Jun N-terminal kinase) and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, differentiation and apoptosis. Overexpression of MKK4 has been associated with aggressive cancer types, including metastatic prostate and ovarian cancer and triple-negative breast cancer. In addition, MKK4 has been identified as a key regulator in liver regeneration. Therefore, MKK4 is a promising target both for cancer therapeutics and for the treatment of liver-associated diseases, offering an alternative to liver transplantation. The recent reports on new inhibitors, as well as the formation of a startup company investigating an inhibitor in clinical trials, show the importance and interest of MKK4 in drug discovery. In this review, we highlight the significance of MKK4 in cancer development and other diseases, as well as its unique role in liver regeneration. Furthermore, we present the most recent progress in MKK4 drug discovery and future challenges in the development of MKK4-targeting drugs. Full article
(This article belongs to the Special Issue Protein and Lipid Kinases: Structure and Function)
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