scholarly journals Phosphoinositide 3-kinase signalling pathways

2001 ◽  
Vol 114 (8) ◽  
pp. 1439-1445 ◽  
Author(s):  
D.A. Cantrell
Keyword(s):  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Subcellular Localisation ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Signalling Molecule ◽  
Inositol Phospholipids ◽  
Wide Range ◽  
Ph Domains ◽  
Phosphoinositide 3 Kinase

Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3′-OH position of the inositol ring of inositol phospholipids, producing three lipid products: PtdIns(3)P, PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). These lipids bind to the pleckstrin homology (PH) domains of proteins and control the activity and subcellular localisation of a diverse array of signal transduction molecules. Three major classes of signalling molecule are regulated by binding of D-3 phosphoinositides to PH domains: guanine-nucleotide-exchange proteins for Ρ family GTPases, the TEC family tyrosine kinases such as BTK and ITK in B and T lymphocytes, respectively, and the AGC superfamily of serine/threonine protein kinases. These molecules are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes, including cell cycle progression, cell growth, cell motility, cell adhesion and cell survival.

scholarly journals Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1

2003 ◽  
Vol 160 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Metello Innocenti ◽  
Emanuela Frittoli ◽  
Isabella Ponzanelli ◽  
John R. Falck ◽  
Saskia M. Brachmann ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Physical Interaction ◽  
Nucleotide Exchange ◽  
Downstream Target ◽  
Signaling Complex ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Phosphoinositide 3 Kinase

Class I phosphoinositide 3-kinases (PI3Ks) are implicated in many cellular responses controlled by receptor tyrosine kinases (RTKs), including actin cytoskeletal remodeling. Within this pathway, Rac is a key downstream target/effector of PI3K. However, how the signal is routed from PI3K to Rac is unclear. One possible candidate for this function is the Rac-activating complex Eps8–Abi1–Sos-1, which possesses Rac-specific guanine nucleotide exchange factor (GEF) activity. Here, we show that Abi1 (also known as E3b1) recruits PI3K, via p85, into a multimolecular signaling complex that includes Eps8 and Sos-1. The recruitment of p85 to the Eps8–Abi1–Sos-1 complex and phosphatidylinositol 3, 4, 5 phosphate (PIP3), the catalytic product of PI3K, concur to unmask its Rac-GEF activity in vitro. Moreover, they are indispensable for the activation of Rac and Rac-dependent actin remodeling in vivo. On growth factor stimulation, endogenous p85 and Abi1 consistently colocalize into membrane ruffles, and cells lacking p85 fail to support Abi1-dependent Rac activation. Our results define a mechanism whereby propagation of signals, originating from RTKs or Ras and leading to actin reorganization, is controlled by direct physical interaction between PI3K and a Rac-specific GEF complex.

scholarly journals The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium

2021 ◽  
Vol 22 (18) ◽  
pp. 10168
Author(s):  
Lanette Kempers ◽  
Amber J. M. Driessen ◽  
Jos van Rijssel ◽  
Martijn A. Nolte ◽  
Jaap D. van Buul
Keyword(s):  
Actin Cytoskeleton ◽  
Cell Function ◽  
Small Gtpases ◽  
Nucleotide Exchange ◽  
Endothelial Cell Function ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Wide Range ◽  
Range Of Functions

Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in the remodeling of the actin cytoskeleton. In the endothelium, they regulate junctional stabilization and play a crucial role in angiogenesis and endothelial barrier integrity. Multiple extracellular signals originating from different vascular processes can influence the activity of Trio and thereby the regulation of the forementioned small GTPases and actin cytoskeleton. This review elucidates how various signals regulate Trio in a distinct manner, resulting in different functional outcomes that are crucial for endothelial cell function in response to inflammation.

Abstract 273: Phosphoinositide 3-Kinase γ Regulates Cardio-protective ERK by Kinase Independent Mechanism

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Maradumane L Mohan ◽  
George Jolly ◽  
Rohit Anand ◽  
Sathyamangla V Naga Prasad
Keyword(s):  
Tyrosine Kinases ◽  
Hek293 Cells ◽  
Independent Function ◽  
Signaling Mechanism ◽  
Erk Activation ◽  
Cellular Processes ◽  
Erk Phosphorylation ◽  
Phosphoinositide 3 Kinase ◽  
Sirna Knockdown

Phosphoinositide 3-kinase (PI3K) enzymes are critical in many cellular processes including survival. PI3Kγ, a member of the PI3K family activated by G-protein coupled receptor (GPCR), is known to be a critical player in activation of extracellular regulated kinase (ERK) signal transduction cascade, a cell survival pathway. However, the exact mechanism by which PI3Kγ plays a role in ERK activation is not clearly understood. Our studies show that PI3Kγ plays a crucial role in enhancing the tone of ERK activation as use of PI3K inhibitors reduced GPCR stimulated ERK phosphorylation in HEK293 cells. siRNA knockdown of PI3Kγ resulted in loss of ERK phosphorylation through GPCRs (β-adrenergic) as well as receptor tyrosine kinases. The role of PI3Kγ in ERK activation was further corroborated by loss of insulin stimulated ERK phosphorylation in PI3Kγ-knockout (KO) mouse embryonic fibroblasts (MEFs). Surprisingly, ERK activation in KO MEFs post-insulin stimulation was completely rescued by expression of kinase-dead PI3Kγ mutant in KO MEFs suggesting a kinase-independent role of PI3Kγ in regulating ERK function. Indepth mechanistic studies showed that PI3Kγ mediated activation of ERK by inhibiting ERK dephosphorylation following stimulation, thus stabilizing the ERK phosphorylation. PI3Kγ physically disrupts the interaction between ERK and ERK dephosphorylating phosphatase PP2A as evidenced by increase in phosphatase association with ERK in KO MEFs. Consistent with this observation, ERK activation was completely abolished in KO MEFs following carvedilol suggesting an essential role for PI3Kγ in cardio-protective ERK activation pathway. In this context, it is known that transverse aortic constriction (TAC) in mice leads to increase in ERK activation in the hearts and is also associated with concurrent up-regulation of PI3Kγ suggesting a key role for kinase-independent function of PI3Kγ in activating and maintaining the ERK signaling cascade. These indepth cellular studies and observation from our TAC studies led us to believe that kinase-dependent function of PI3Kγ may contribute to pathology while kinase-independent function may be cardio-protective through inhibition of PP2A by PI3Kγ. This novel signaling mechanism by PI3Kγ will be presented.

scholarly journals Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling

1998 ◽  
Vol 333 (3) ◽  
pp. 471-490 ◽  
Author(s):  
Peter R. SHEPHERD ◽  
Dominic J. WITHERS ◽  
Kenneth SIDDLE
Keyword(s):  
Protein Kinase ◽  
Insulin Signalling ◽  
Protein Substrates ◽  
Cellular Processes ◽  
Glucose And Lipid Metabolism ◽  
Wide Range ◽  
Dependent Protein ◽  
Switch Mechanism ◽  
Phosphoinositide 3 Kinase ◽  
Allosteric Regulators

Insulin plays a key role in regulating a wide range of cellular processes. However, until recently little was known about the signalling pathways that are involved in linking the insulin receptor with downstream responses. It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK. Using mechanisms such as this, PI 3-kinase is able to act as a molecular switch to regulate the activity of serine/threonine-specific kinase cascades important in mediating insulin's effects on endpoint responses.

scholarly journals New Functions of Vav Family Proteins in Cardiovascular Biology, Skeletal Muscle, and the Nervous System

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 857
Author(s):  
Sonia Rodríguez-Fdez ◽  
L. Francisco Lorenzo-Martín ◽  
Salvatore Fabbiano ◽  
Mauricio Menacho-Márquez ◽  
Vincent Sauzeau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tyrosine Kinases ◽  
Rho Gtpases ◽  
Signaling Proteins ◽  
Nucleotide Exchange ◽  
Molecular Scaffolds ◽  
Cellular Processes ◽  
Nucleotide Exchange Factors ◽  
Cardiovascular Biology ◽  
Regulation Of Blood Pressure

Vav proteins act as tyrosine phosphorylation-regulated guanosine nucleotide exchange factors for Rho GTPases and as molecular scaffolds. In mammals, this family of signaling proteins is composed of three members (Vav1, Vav2, Vav3) that work downstream of protein tyrosine kinases in a wide variety of cellular processes. Recent work with genetically modified mouse models has revealed that these proteins play key signaling roles in vascular smooth and skeletal muscle cells, specific neuronal subtypes, and glia cells. These functions, in turn, ensure the proper regulation of blood pressure levels, skeletal muscle mass, axonal wiring, and fiber myelination events as well as systemic metabolic balance. The study of these mice has also led to the discovery of new physiological interconnection among tissues that contribute to the ontogeny and progression of different pathologies such as, for example, hypertension, cardiovascular disease, and metabolic syndrome. Here, we provide an integrated view of all these new Vav family-dependent signaling and physiological functions.

Beyond calcium: new signaling pathways for Tec family kinases

2002 ◽  
Vol 115 (15) ◽  
pp. 3039-3048 ◽  
Author(s):  
Aya Takesono ◽  
Lisa D. Finkelstein ◽  
Pamela L. Schwartzberg
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cellular Transformation ◽  
Antigen Receptors ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Tec Kinases ◽  
Wide Range

The Tec kinases represent the second largest family of mammalian non-receptor tyrosine kinases and are distinguished by the presence of distinct proline-rich regions and pleckstrin homology domains that are required for proper regulation and activation. Best studied in lymphocyte and mast cells, these kinases are critical for the full activation of phospholipase-C γ (PLC-γ) and Ca2+ mobilization downstream of antigen receptors. However, it has become increasingly clear that these kinases are activated downstream of many cell-surface receptors,including receptor tyrosine kinases, cytokine receptors, integrins and G-protein-coupled receptors. Evidence suggests that the Tec kinases influence a wide range of signaling pathways controlling activation of MAP kinases,actin reorganization, transcriptional regulation, cell survival and cellular transformation. Their impact on cellular physiology suggests that the Tec kinases help regulate multiple cellular processes beyond Ca2+mobilization.

scholarly journals The low complexity regions in the C-terminus are essential for the subcellular localisation of Leishmania casein kinase 1 but not for its activity

2020 ◽  
Author(s):  
Daniel Martel ◽  
Stewart Pine ◽  
Katharina Bartsch ◽  
Joachim Clos ◽  
Gerald F. Späth ◽  
...  
Keyword(s):  
Host Cell ◽  
Membrane Trafficking ◽  
Low Complexity ◽  
Casein Kinase ◽  
Subcellular Localisation ◽  
Casein Kinase 1 ◽  
Cellular Processes ◽  
C Terminus ◽  
Wide Range ◽  
Eukaryotic Organisms

AbstractCasein Kinase 1 (CK1) family members are serine/threonine protein kinases ubiquitously expressed in eukaryotic organisms. They are involved in a wide range of important cellular processes, such as membrane trafficking, or vesicular transport in organisms from yeast to humans. Due to its broad spectrum of action, CK1 activity and expression is tightly regulated by a number of mechanisms, including subcellular sequestration. Defects in CK1 regulation, localisation or the introduction of mutations in the CK1 coding sequence are often associated with important diseases such as cancer. Increasing evidence suggest that the manipulation of host cell CK1 signalling pathways by intracellular pathogens, either by exploiting the host CK1 or by exporting the CK1 of the pathogen into the host cell may play an important role in infectious diseases. Leishmania CK1.2 is essential for parasite survival and released into the host cell, playing an important role in host pathogen interactions. Although Leishmania CK1.2 has dual role in the parasite and in the host cell, nothing is known about its parasitic localisation and organelle-specific functions. In this study, we show that CK1.2 is a ubiquitous kinase, which is present in the cytoplasm, associated to the cytoskeleton and localised to various organelles, indicating potential roles in kinetoplast and nuclear segregation, as well as ribosomal processing and motility. Furthermore, using truncated mutants, we show for the first time that the two low complexity regions (LCR) present in the C-terminus of CK1.2 are essential for the subcellular localisation of CK1.2 but not for its kinase activity, whereas the deletion of the N-terminus leads to a dramatic decrease in CK1.2 abundance. In conclusion, our data on the localisation and regulation of Leishmania CK1.2 contribute to increase the knowledge on this essential kinase and get insights into its role in the parasite.

The regulation of membrane to cytosol partitioning of signalling proteins by phosphoinositides and their soluble headgroups

2005 ◽  
Vol 33 (6) ◽  
pp. 1303-1307 ◽  
Author(s):  
C.P. Downes ◽  
A. Gray ◽  
A. Fairservice ◽  
S.T. Safrany ◽  
I.H. Batty ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Inositol Phosphates ◽  
Nucleotide Exchange ◽  
Ph Domain ◽  
Inositol Polyphosphates ◽  
Signalling Molecules ◽  
Nucleotide Exchange Factor ◽  
Inositol Phospholipids ◽  
Ph Domains ◽  
Pi Ligands

Inositol phospholipids [PIs (phosphoinositides)] represent a group of membrane-tethered signalling molecules which differ with respect to the number and distribution of monoester phosphate groups around the inositol ring. They function by binding to proteins which possess one of several domains that bind a particular PI species, often with high affinity and specificity. PH (pleckstrin homology) domains for example possess ligand-binding pockets that are often lined with positively charged residues and which bind PIs with varying degrees of specificity. Several PH domains bind not only PIs, but also their cognate headgroups, many of which occur naturally in cells as relatively abundant cytosolic inositol phosphates. The subcellular distributions of proteins possessing such PH domains are therefore determined by the relative levels of competing membrane-bound and soluble ligands. A classic example of the latter is the PH domain of phospholipase Cδ1, which binds both phosphatidylinositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate. We have shown that the N-terminal PH domain of the Rho family guanine nucleotide-exchange factor, Tiam 1, binds PI ligands promiscuously allowing multiple modes of regulation. We also recently analysed the ligand-binding specificity of the PH domain of PI-dependent kinase 1 and found that it could bind abundant inositol polyphosphates such as inositol hexakisphosphate. This could explain the dual distribution of this key signalling component, which needs to access substrates at both the plasma membrane and in the cytosol.

Heterocyclization of 2-(2-phenylhydrazono)cyclohexane-1,3-dione to Synthesis Thiophene, Pyrazole and 1,2,4-triazine Derivatives with Anti-Tumor and Tyrosine Kinase Inhibitions

2020 ◽  
Vol 20 (10) ◽  
pp. 1209-1220
Author(s):  
Rafat M. Mohareb ◽  
Ensaf S. Alwan
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Tyrosine Kinases ◽  
Proliferative Activity ◽  
Cancer Cell Lines ◽  
Thiazole Derivatives ◽  
Wide Range ◽  
Cytotoxic Compounds ◽  
Triazine Derivatives ◽  
Target Molecules

Background: Recently tetrahydrobenzo[b]thiazole derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the thiazole nucleus were known. Objective: This work aimed to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. The target molecules were obtained starting from the arylhydrazonocyclohexan-1,3-dione followed by their heterocyclization reactions to produce anticancer target molecules. Methods: The arylhydrazone derivatives 3a-c underwent different heterocyclization reactions to produce thiophene, thiazole, pyrazole and 1,2,4-triazine derivatives. The anti-proliferative activity of twenty six compounds among the synthesized compounds toward the six cancer cell lines namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. Results: Anti-proliferative evaluations, tyrosine and Pim-1 kinase inhibitions were perform for most of the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. Conclusion: The compounds with high anti-proliferative activity towards the cancer cell lines showed that compounds 3b, 3c, 5e, 5f, 8c, 9c, 11c, 12c, 14e, 14f and 16c were the most cytotoxic compounds. Further tests of the latter compounds toward the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 5e, 5f, 8c, 9c, 12c, 14e, 14f and 16c were the most potent of the tested compounds toward the five tyrosine kinases and compounds 6d, 11a, 20b and 21e were of the highest inhibitions towards Pim-1 kinase. Pan Assay Interference Compounds (PAINS) for the most cytotoxic compounds showed zero PAINS alert and can be used as lead compounds.

Saccharomyces cerevisiae SSD1-VConfers Longevity by a Sir2p-Independent Mechanism

Genetics ◽  
2004 ◽  
Vol 166 (4) ◽  
pp. 1661-1672 ◽  
Author(s):  
Matt Kaeberlein ◽  
Alex A Andalis ◽  
Gregory B Liszt ◽  
Gerald R Fink ◽  
Leonard Guarente
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Life Span ◽  
Cell Cycle Progression ◽  
Polymorphic Locus ◽  
Cell Integrity ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Maximal Life Span ◽  
Independent Mechanism ◽  
Yeast Aging

AbstractThe SSD1 gene of Saccharomyces cerevisiae is a polymorphic locus that affects diverse cellular processes including cell integrity, cell cycle progression, and growth at high temperature. We show here that the SSD1-V allele is necessary for cells to achieve extremely long life span. Furthermore, addition of SSD1-V to cells can increase longevity independently of SIR2, although SIR2 is necessary for SSD1-V cells to attain maximal life span. Past studies of yeast aging have been performed in short-lived ssd1-d strain backgrounds. We propose that SSD1-V defines a previously undescribed pathway affecting cellular longevity and suggest that future studies on longevity-promoting genes should be carried out in long-lived SSD1-V strains.

Sign in / Sign up

Export Citation Format

Share Document