A cascade involving p85, Cdc42 and septin 2 regulates cytokinesis

2007 ◽  
Vol 35 (2) ◽  
pp. 222-224 ◽  
Author(s):  
V. Silió ◽  
M. Marqués ◽  
I. Cortés ◽  
S. Zuluaga ◽  
A.C. Carrera
Keyword(s):  
Cell Separation ◽  
Nuclear Division ◽  
Growth Factor Receptor ◽  
Regulatory Subunit ◽  
Final Phase ◽  
Receptor Stimulation ◽  
Pi3k Activity ◽  
Phosphoinositide 3 Kinase ◽  
The Impact ◽  
Early Mitosis

Mitosis, the final phase of cell division, includes the processes of nuclear division and cytosolic division (cytokinesis). Cytokinesis occurs when DNA separation terminates, and involves a number of proteins that induce furrowing at the region of cell separation, formation of new membrane, and abscission. This process is remarkably complex, and the list of proteins that regulate it is long. Our understanding is limited as to how these players are organized in space and time to ensure that the cytosol divides equally, and only after nuclear division. Class IA PI3K (phosphoinositide 3-kinase) is an enzyme activated by growth factor receptor stimulation, but it is re-activated in early mitosis and regulates mitosis entry. By the end of mitosis, PI3K activity is low; at this point, the class IA PI3K regulatory subunit p85 contributes to co-ordination of the cytoskeletal changes required for cytokinesis. The impact of these observations on current models of cytokinesis execution is discussed here.

The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase

2008 ◽  
Vol 413 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Nobuo Tsuboi ◽  
Tadahiko Utsunomiya ◽  
Richard L. Roberts ◽  
Hideyuki Ito ◽  
Keiko Takahashi ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Regulatory Subunit ◽  
Mutant Form ◽  
Dependent Manner ◽  
Screening Assay ◽  
Intact Cells ◽  
Pi3k Activity ◽  
Phosphoinositide 3 Kinase

CD148 is a transmembrane tyrosine phosphatase that has been implicated in the regulation of cell growth and transformation. However, the signalling mechanisms of CD148 are incompletely understood. To identify the specific intracellular molecules involved in CD148 signalling, we carried out a modified yeast two-hybrid screening assay. Using the substrate-trapping mutant form of CD148 (CD148 D/A) as bait, we recovered the p85 regulatory subunit of PI3K (phosphoinositide 3-kinase). CD148 D/A, but not catalytically active CD148, interacted with p85 in a phosphorylation-dependent manner in vitro and in intact cells. Growth factor receptor and PI3K activity were also trapped by CD148 D/A via p85 from pervanadate-treated cell lysates. CD148 prominently and specifically dephosphorylated p85 in vitro. Co-expression of CD148 reduced p85 phosphorylation induced by active Src, and attenuated the increases in PI3K activity, yet CD148 did not alter the basal PI3K activity. Finally, CD148 knock-down by siRNA (short interfering RNA) increased PI3K activity on serum stimulation. Taken together, these results demonstrate that CD148 may interact with and dephosphorylate p85 when it is phosphorylated and modulate the magnitude of PI3K activity.

scholarly journals Interaction of Ras with phosphoinositide 3-kinase γ

1997 ◽  
Vol 326 (3) ◽  
pp. 891-895 ◽  
Author(s):  
Ignacio RUBIO ◽  
Pablo RODRIGUEZ-VICIANA ◽  
Julian DOWNWARD ◽  
Reinhard WETZKER
Keyword(s):  
Binding Site ◽  
G Proteins ◽  
Terminal Region ◽  
Regulatory Subunit ◽  
Heterotrimeric G Proteins ◽  
Modest Increase ◽  
Pi3k Activity ◽  
Phosphoinositide 3 Kinase ◽  
Stimulation Of

Phosphoinositide 3-kinase γ (PI3Kγ) can be activated in vitro by both α and βγ subunits of heterotrimeric G-proteins and does not interact with p85, the regulatory subunit of PI3Kα. Here we demonstrate the binding of Ras to PI3Kγ in vitro. An N-terminal region of PI3Kγ was identified as a binding site for Ras. After co-expression with PI3Kγ in COS-7 cells, Ras induced only a modest increase in PI3K activity compared with the stimulation of PI3Kα by Ras in the same cells.

scholarly journals Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110α and β by protease-activated receptor 2 and β-arrestins

2007 ◽  
Vol 408 (2) ◽  
pp. 221-230 ◽  
Author(s):  
Ping Wang ◽  
Puneet Kumar ◽  
Chang Wang ◽  
Kathryn A. DeFea
Keyword(s):  
G Protein ◽  
Small Gtpase ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Catalytic Subunits ◽  
Pi3k Activity ◽  
Phosphoinositide 3 Kinase ◽  
Protease Activated Receptor 2

PAR-2 (protease-activated receptor 2) is a GPCR (G-protein-coupled receptor) that can elicit both G-protein-dependent and -independent signals. We have shown previously that PAR-2 simultaneously promotes Gαq/Ca2+-dependent activation and β-arrestin-1-dependent inhibition of class IA PI3K (phosphoinositide 3-kinase), and we sought to characterize further the role of β-arrestins in the regulation of PI3K activity. Whereas the ability of β-arrestin-1 to inhibit p110α (PI3K catalytic subunit α) has been demonstrated, the role of β-arrestin-2 in PI3K regulation and possible differences in the regulation of the two catalytic subunits (p110α and p110β) associated with p85α (PI3K regulatory subunit) have not been examined. In the present study we have demonstrated that: (i) PAR-2 increases p110α- and p110β-associated lipid kinase activities, and both p110α and p110β are inhibited by over-expression of either β-arrestin-1 or -2; (ii) both β-arrestin-1 and -2 directly inhibit the p110α catalytic subunit in vitro, whereas only β-arrestin-2 directly inhibited p110β; (iii) examination of upstream pathways revealed that PAR-2-induced PI3K activity required the small GTPase Cdc (cell-division cycle)42, but not tyrosine phosphorylation of p85; and (iv) β-arrestins inhibit PAR-2-induced Cdc42 activation. Taken together, these results indicated that β-arrestins could inhibit PAR-2-stimulated PI3K activity, both directly and through interference with upstream pathways, and that the two β-arrestins differ in their ability to inhibit the p110α and p110β catalytic subunits. These results are particularly important in light of the growing interest in PAR-2 as a pharmacological target, as commonly used biochemical assays that monitor G-protein coupling would not screen for β-arrestin-dependent signalling events.

A novel signaling pathway for β-adrenergic receptor-mediated activation of phosphoinositide 3-kinase in H9c2 cardiomyocytes

2007 ◽  
Vol 293 (1) ◽  
pp. H385-H393 ◽  
Author(s):  
Naohiro Yano ◽  
Vlad Ianus ◽  
Ting C. Zhao ◽  
Andy Tseng ◽  
James F. Padbury ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
Mouse Heart ◽  
Pi3k Activity ◽  
H9c2 Cardiomyocytes ◽  
Phosphoinositide 3 Kinase

Stimulation of cardiac β-adrenergic receptors (β-AR) activates both the Gs- and Gi-coupled signaling cascades, including the phosphoinositide 3 kinase (PI3K) pathway, that have important physiological implications. Multiple isoforms of PI3K exist in the heart. The goals of this study were to examine the intracellular signaling pathways linking β-AR to PI3K and to identify the PI3K isoform mediating this transactivation in a cardiac context. Acute β-AR stimulation with isoproterenol resulted in increased tyrosine kinase-associated PI3K activity and phosphorylation of Akt and p70S6K in H9c2 cardiomyocytes. Cotreatment with ICI-118,551, but not CGP-20712, abolished the increase in PI3K activity, suggesting a β2-AR-mediated event. PI3K activation was also abrogated by cotreatment with pertussis toxin, 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolol[3,4-d]pyrimidine (PP2, a selective Src-family tyrosine kinases inhibitor), or AG-1296 [selective platelet-derived growth factor receptor (PDGFR) inhibitor] but not with an inhibitor for protein kinase A, protein kinase C, Ras, adenylyl cyclase, epidermal growth factor receptor, or insulin-like growth factor-1 receptor. β-AR stimulation induced an increase in tyrosine phosphorylation of PDGFR, which was abolished by inhibition of Src either by PP2 or small interfering RNA. Moreover, H9c2 cardiomyocytes stably transfected with a vector expressing a Gβγ sequestrant peptide derived from the COOH-terminus of β-AR kinase-1 failed to activate PI3K after β-AR stimulation, suggesting Gβγ is required for the transactivation. Furthermore, acute β-AR stimulation in vivo resulted in increases in PDGFR-associated PI3K and PI3Kα isoform activities but not the activities of other isoforms (PI3Kβ, -δ, -γ) in adult mouse heart. Taken together, these data provide in vitro and in vivo evidence for a novel mechanism of β-AR-mediated transactivation of cardiac PI3Kα via sequential involvement of Gαi/Gβγ, Src, and PDGFR.

scholarly journals Role of the Pi3k Regulatory Subunit in the Control of Actin Organization and Cell Migration

2000 ◽  
Vol 151 (2) ◽  
pp. 249-262 ◽  
Author(s):  
Concepción Jiménez ◽  
Rosario Armas Portela ◽  
Mario Mellado ◽  
Jose Miguel Rodríguez-Frade ◽  
John Collard ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cellular Response ◽  
Actin Dynamics ◽  
Regulatory Subunit ◽  
Actin Stress Fiber ◽  
Pdgf Receptor ◽  
Receptor Stimulation ◽  
Actin Organization ◽  
Phosphoinositide 3 Kinase

Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85α regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85α in controlling PDGF receptor–induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics.

scholarly journals Activated STAT5 proteins induce activation of the PI 3-kinase/Akt and Ras/MAPK pathways via the Gab2 scaffolding adapter

2005 ◽  
Vol 390 (1) ◽  
pp. 359-366 ◽  
Author(s):  
Rémy Nyga ◽  
Christian Pecquet ◽  
Noria Harir ◽  
Haihua Gu ◽  
Isabelle Dhennin-Duthille ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Janus Kinase ◽  
Scaffolding Protein ◽  
Regulatory Subunit ◽  
Growth And Survival ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

The active forms of STAT5A (signal transducer and activator of transcription 5A) and STAT5B are able to relieve the cytokine dependence of haematopoietic cells and to induce leukaemia in mice. We have demonstrated previously that activation of the PI3K (phosphoinositide 3-kinase) signalling cascade plays a major role in cell growth and survival induced by these proteins. Interaction between STAT5 and p85, the regulatory subunit of the PI3K, has been suggested to be required for this activation. We show in the present study that the scaffolding protein Gab2 [Grb2 (growth-factor-receptor-bound protein 2)-associated binder-2] is an essential component of this interaction. Gab2 is persistently tyrosine-phosphorylated in Ba/F3 cells expressing caSTAT5 (constitutively activated STAT5), independent of JAK2 (Janus kinase 2) activation where it interacts with STAT5, p85 and Grb2, but not with Shp2 [SH2 (Src homology 2)-domain-containing tyrosine phosphatase] proteins. Interaction of STAT5 with Gab2 was also observed in Ba/F3 cells stimulated with interleukin-3 or expressing the oncogenic fusion protein Tel–JAK2. The MAPKs (mitogen-activated protein kinases) ERK1 (extracellular-signal-regulated kinase 1) and ERK2 were constitutively activated in the caSTAT5-expressing cells and were found to be required for caSTAT5-induced cell proliferation. Overexpression of Gab2-3YF, a mutant of Gab2 incapable of binding PI3K, inhibited the proliferation and survival of caSTAT5-expressing cells as well as ERK1/2 and Akt/protein kinase B phosphorylation. Taken together, our results indicate that Gab2 is required for caSTAT5-induced cell proliferation by regulating both the PI3K/Akt and the Ras/MAPK pathways.

The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario?

2018 ◽  
Vol 18 (6) ◽  
pp. 832-836
Author(s):  
Giuseppe Buono ◽  
Francesco Schettini ◽  
Francesco Perri ◽  
Grazia Arpino ◽  
Roberto Bianco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Translational Research ◽  
Cell Biology ◽  
Cancer Biology ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Molecular Heterogeneity ◽  
Therapeutic Implications ◽  
The Impact

Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors “omics”, including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker-driven adaptive studies, may represent a turning point for BC translational research. </P><P> It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

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