Promising Molecular Targets for Design of Antitumor Drugs Based on Ras Protein Signaling Cascades

The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

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Regulators of G protein Signaling (RGS) proteins (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f891/2020.4 ◽

2020 ◽

Vol 2020 (4) ◽

Author(s):

Katelin E. Ahlers-Dannen ◽

Mohammed Alqinyah ◽

Christopher Bodle ◽

Josephine Bou Dagher ◽

Bandana Chakravarti ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Signaling Cascades ◽

G Protein Signaling ◽

Rgs Proteins ◽

Protein Signaling ◽

Heterotrimeric G Proteins ◽

Gtp Hydrolysis ◽

Rgs Domain ◽

G Protein Coupled

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [160, 377, 411, 415, 416, 512, 519, 312, 6].

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Regulators of G protein Signaling (RGS) proteins (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f891/2020.5 ◽

2020 ◽

Vol 2020 (5) ◽

Author(s):

Katelin E. Ahlers-Dannen ◽

Mohammed Alqinyah ◽

Christopher Bodle ◽

Josephine Bou Dagher ◽

Bandana Chakravarti ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Signaling Cascades ◽

G Protein Signaling ◽

Rgs Proteins ◽

Protein Signaling ◽

Heterotrimeric G Proteins ◽

Gtp Hydrolysis ◽

Rgs Domain ◽

G Protein Coupled

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [183, 411, 446, 450, 451, 558, 566, 345, 9].

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Harnessing the Parathyroid Hormone, Wnt, and Bone Morphogenetic Protein Signaling Cascades for Successful Bone Tissue Engineering

Tissue Engineering Part B Reviews ◽

10.1089/ten.teb.2011.0265 ◽

2011 ◽

Vol 17 (6) ◽

pp. 475-479 ◽

Cited By ~ 13

Author(s):

Vicki Rosen

Keyword(s):

Tissue Engineering ◽

Parathyroid Hormone ◽

Bone Tissue Engineering ◽

Bone Morphogenetic Protein ◽

Bone Tissue ◽

Signaling Cascades ◽

Protein Signaling ◽

Bone Morphogenetic Protein Signaling ◽

Morphogenetic Protein

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Ubiquitin in the activation and attenuation of innate antiviral immunity

Journal of Experimental Medicine ◽

10.1084/jem.20151531 ◽

2015 ◽

Vol 213 (1) ◽

pp. 1-13 ◽

Cited By ~ 97

Author(s):

Steven M. Heaton ◽

Natalie A. Borg ◽

Vishva M. Dixit

Keyword(s):

Host Cells ◽

Signaling Cascades ◽

Type I ◽

Protein Signaling ◽

Toll Like Receptor ◽

Antiviral Signaling ◽

Modification System ◽

Innate Antiviral Immunity ◽

Inducible Gene ◽

Oligomerization Domain

Viral infection activates danger signals that are transmitted via the retinoic acid–inducible gene 1–like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression.

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Regulators of G protein Signaling (RGS) proteins in GtoPdb v.2021.2

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f891/2021.2 ◽

2021 ◽

Vol 2021 (2) ◽

Author(s):

Katelin E. Ahlers-Dannen ◽

Mohammed Alqinyah ◽

Christopher Bodle ◽

Josephine Bou Dagher ◽

Bandana Chakravarti ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Signaling Cascades ◽

G Protein Signaling ◽

Rgs Proteins ◽

Protein Signaling ◽

Heterotrimeric G Proteins ◽

Gtp Hydrolysis ◽

Rgs Domain ◽

G Protein Coupled

Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein-coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP-bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [225, 529, 578, 583, 584, 742, 753, 444, 10].

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Synthetic Retinoids as Potential Therapeutics in Prostate Cancer—An Update of the Last Decade of Research: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms221910537 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10537

Author(s):

Przemysław Hałubiec ◽

Agnieszka Łazarczyk ◽

Oskar Szafrański ◽

Torsten Bohn ◽

Joanna Dulińska-Litewka

Keyword(s):

Prostate Cancer ◽

Retinoic Acid ◽

Experimental Studies ◽

Molecular Targets ◽

Antitumor Drugs ◽

Management Options ◽

Castration Resistant ◽

Current State ◽

Derivatives Of ◽

Potential Therapeutics

Prostate cancer (PC) is the second most common tumor in males. The search for appropriate therapeutic options against advanced PC has been in process for several decades. Especially after cessation of the effectiveness of hormonal therapy (i.e., emergence of castration-resistant PC), PC management options have become scarce and the prognosis is poor. To overcome this stage of disease, an array of natural and synthetic substances underwent investigation. An interesting and promising class of compounds constitutes the derivatives of natural retinoids. Synthesized on the basis of the structure of retinoic acid, they present unique and remarkable properties that warrant their investigation as antitumor drugs. However, there is no up-to-date compilation that consecutively summarizes the current state of knowledge about synthetic retinoids with regard to PC. Therefore, in this review, we present the results of the experimental studies on synthetic retinoids conducted within the last decade. Our primary aim is to highlight the molecular targets of these compounds and to identify their potential promise in the treatment of PC.

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