scholarly journals Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 2952-2961 ◽  
Author(s):  
Philip J. S. Stork ◽  
Tara J. Dillon
Keyword(s):  
Map Kinase ◽  
G Protein ◽  
Protein Function ◽  
Cell Function ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Myelogenous Leukemia ◽  
Critical Control Points ◽  
Small G Protein ◽  
Wide Range

AbstractSmall G proteins serve as critical control points in signal transduction, integrating a wide range of stimuli to dictate discrete cellular outcomes. The outcomes of small G-protein signaling can both potentiate and antagonize one another. Studies in hematopoietic cells have uncovered multiple functions for the small G protein, Rap1 (Ras-proximate-1). Because Rap1 can regulate cell proliferation, differentiation, and adhesion through distinct mechanisms, it serves as a paradigm for the need for tight cellular control of small G-protein function. Rap1 has received recent attention for its role in enhancing integrin-dependent signals. This action of Rap1 augments a variety of processes that characterize hematopoietic-cell function, including aggregation, migration, extravasation, and homing to target tissues. Rap1 may also regulate cellular differentiation and proliferation via pathways that are distinct from those mediating adhesion, and involve regulation of the mitogen-activated protein (MAP) kinase or ERK (extracellular signal-regulated kinase) cascade. These actions of Rap1 occur in selected cell types to enhance or diminish ERK signaling, depending on the expression pattern of the MAP kinase kinase kinases of the Raf family: Raf-1 and B-Raf. This review will examine the functions of Rap1 in hematopoietic cells, and focus on 3 cellular scenarios where the multiple actions of Rap1 function have been proposed. Recent studies implicating Rap1 in the maturation of megakaryocytes, the pathogenesis of chronic myelogenous leukemia (CML), and activation of peripheral T cells will receive particular attention.

Yeast Small G-Protein Function

2010 ◽  
pp. 1813-1817
Author(s):  
Keith G. Kozminski ◽  
Hay-Oak Park
Keyword(s):  
G Protein ◽  
Protein Function ◽  
Small G Protein

scholarly journals Functions of c-Jun in Liver and Heart Development

1999 ◽  
Vol 145 (5) ◽  
pp. 1049-1061 ◽  
Author(s):  
Robert Eferl ◽  
Maria Sibilia ◽  
Frank Hilberg ◽  
Andrea Fuchsbichler ◽  
Iris Kufferath ◽  
...  
Keyword(s):  
Heart Development ◽  
Target Genes ◽  
Cell Function ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Neural Crest Cell ◽  
Cell Types ◽  
Keratin 18 ◽  
Nuclear Factor 1 ◽  
Factor C

Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0 but little is known about the cell types affected as well as the cause of embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts, whereas the expression of 15 mRNAs, including those of albumin, keratin 18, hepatocyte nuclear factor 1, β-globin, and erythropoietin, some of which are putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in mutant livers is most likely not due to a cell-autonomous defect, since c-jun−/− fetal liver cells are able to reconstitute all hematopoietic compartments of lethally irradiated recipient mice. A developmental analysis of chimeras showed contribution of c-jun−/− ES cell derivatives to fetal, but not to adult livers, suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the reduced mitotic and increased apoptotic rates found in primary liver cell cultures derived from c-jun−/− fetuses. Furthermore, a novel function for c-Jun was found in heart development. The heart outflow tract of c-jun−/− fetuses show malformations that resemble the human disease of a truncus arteriosus persistens. Therefore, the lethality of c-jun mutant fetuses is most likely due to pleiotropic defects reflecting the diversity of functions of c-Jun in development, such as a role in neural crest cell function, in the maintenance of hepatic hematopoiesis and in the regulation of apoptosis.

scholarly journals Nonmyristoylated Abl proteins transform a factor-dependent hematopoietic cell line.

1992 ◽  
Vol 12 (4) ◽  
pp. 1864-1871 ◽  
Author(s):  
G Q Daley ◽  
R A Van Etten ◽  
P K Jackson ◽  
A Bernards ◽  
D Baltimore
Keyword(s):  
Plasma Membrane ◽  
Cell Line ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Hematopoietic Cell ◽  
Myelogenous Leukemia ◽  
3T3 Fibroblasts ◽  
Nih 3T3

N-terminal myristoylation can promote the association of proteins with the plasma membrane, a property that is required for oncogenic variants of Src and Abl to transform fibroblastic cell types. The P210bcr/abl protein of chronic myelogenous leukemia cells is not myristoylated and does not stably transform NIH 3T3 fibroblasts; however, it will transform lymphoid and myeloid cell types in vitro and in vivo, suggesting that myristoylation is not required for Abl variants to transform hematopoietic cells. To test this hypothesis, we introduced point mutations that disrupt myristoylation into two activated Abl proteins, v-Abl and a deletion mutant of c-Abl (delta XB), and examined their ability to transform an interleukin-3-dependent lymphoblastoid cell line, Ba/F3. Neither of the nonmyristoylated Abl proteins transformed NIH 3T3 fibroblasts, but like P210bcr/abl, both were capable of transforming the Ba/F3 cells to factor independence and tumorigenicity. Nonmyristoylated Abl variants did not associate with the plasma membrane in the transformed Ba/F3 cells. These results demonstrate that Abl proteins can transform hematopoietic cells in the absence of membrane association and suggest that distinct functions of Abl are required for transformation of fibroblast and hematopoietic cell types.

scholarly journals Reciprocal regulation of two G protein-coupled receptors sensing extracellular concentrations of Ca2+ and H+

2015 ◽  
Vol 112 (34) ◽  
pp. 10738-10743 ◽  
Author(s):  
Wei-Chun Wei ◽  
Benjamin Jacobs ◽  
Esther B. E. Becker ◽  
Maike D. Glitsch
Keyword(s):  
G Protein ◽  
Interstitial Fluid ◽  
Cell Function ◽  
G Protein Coupled Receptors ◽  
Dependent Manner ◽  
Reciprocal Regulation ◽  
Surface Receptors ◽  
Wide Range ◽  
The Difference ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are cell surface receptors that detect a wide range of extracellular messengers and convey this information to the inside of cells. Extracellular calcium-sensing receptor (CaSR) and ovarian cancer gene receptor 1 (OGR1) are two GPCRs that sense extracellular Ca2+ and H+, respectively. These two ions are key components of the interstitial fluid, and their concentrations change in an activity-dependent manner. Importantly, the interstitial fluid forms part of the microenvironment that influences cell function in health and disease; however, the exact mechanisms through which changes in the microenvironment influence cell function remain largely unknown. We show that CaSR and OGR1 reciprocally inhibit signaling through each other in central neurons, and that this is lost in their transformed counterparts. Furthermore, strong intracellular acidification impairs CaSR function, but potentiates OGR1 function. Thus, CaSR and OGR1 activities can be regulated in a seesaw manner, whereby conditions promoting signaling through one receptor simultaneously inhibit signaling through the other receptor, potentiating the difference in their relative signaling activity. Our results provide insight into how small but consistent changes in the ionic microenvironment of cells can significantly alter the balance between two signaling pathways, which may contribute to disease progression.

scholarly journals Mechanisms of Statin-mediated Inhibition of Small G-protein Function

2005 ◽  
Vol 280 (40) ◽  
pp. 34202-34209 ◽  
Author(s):  
Andrew Cordle ◽  
Jessica Koenigsknecht-Talboo ◽  
Brandy Wilkinson ◽  
Allison Limpert ◽  
Gary Landreth
Keyword(s):  
G Protein ◽  
Protein Function ◽  
Small G Protein

Relationship between Na(+),K(+)-ATPase and cell attachment

1999 ◽  
Vol 112 (23) ◽  
pp. 4223-4232 ◽  
Author(s):  
R.G. Contreras ◽  
L. Shoshani ◽  
C. Flores-Maldonado ◽  
A. Lazaro ◽  
M. Cereijido
Keyword(s):  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
G Protein ◽  
Protein Tyrosine Kinase ◽  
Cell Attachment ◽  
Mdck Cells ◽  
Gtpase Activating Protein ◽  
High Affinity ◽  
Small G Protein ◽  
Map Kinase Kinase

A prolonged ouabain blockade of the Na(+),K(+)-ATPase detaches cells from each other and from the substrate. This suggests the existence of a link between pump (P) and attachment (A). In the present work, we report that MDCK-W cells treated with ouabain increase tyrosine phosphorylation and content of active MAP kinase, redistribute molecules involved in cell attachment (occludin, ZO-1, desmoplakin, cytokeratin, alpha-actinin, vinculin and actin), and detach. Genistein and UO126, inhibitors of protein tyrosine kinase and of MAP kinase kinase, respectively, block this detachment. The content of P190(Rho-GAP), a GTPase activating protein of the Rho small G-protein subfamily, is increased by ouabain, suggesting that both the Rho/Rac and MAPK pathways are involved. Another clone of MDCK cells whose Na(+),K(+)-ATPase has a negligible affinity for the drug, show none of the effects described for MDCK-W and remain attached. Ma104 cells, a line that has a high affinity for ouabain and stops pumping, fail to modify phosphorylation, as well as the pattern of distribution of attaching molecules, and remain in the monolayer. Taken together, these results suggest that there is a mechanism (P-->A) that transduces a blockade of the pump in a detachment of the cell from neighbors and substrate, in which Ma104 cells are faulty.

scholarly journals Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1

2001 ◽  
Vol 21 (11) ◽  
pp. 3671-3683 ◽  
Author(s):  
John M. Schmitt ◽  
Philip J. S. Stork
Keyword(s):  
Cyclic Amp ◽  
Map Kinase ◽  
G Protein ◽  
Cell Cycle Progression ◽  
3T3 Cells ◽  
Small G Protein ◽  
Map Kinase Cascade ◽  
Kinase Cascade ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT In many normal and transformed cell types, the intracellular second messenger cyclic AMP (cAMP) blocks the effects of growth factors and serum on mitogenesis, proliferation, and cell cycle progression. cAMP exerts these growth-inhibitory effects via inhibition of the mitogen-activated protein (MAP) kinase cascade. Here, using Hek293 and NIH 3T3 cells, we show that cAMP's inhibition of the MAP kinase cascade is mediated by the small G protein Rap1. Activation of Rap1 by cAMP induces the association of Rap1 with Raf-1 and limits Ras-dependent activation of ERK. In NIH 3T3 cells, Rap1 is required not only for cAMP's inhibition of ERK activation but for inhibition of cell proliferation and mitogenesis as well.

scholarly journals Nonmyristoylated Abl proteins transform a factor-dependent hematopoietic cell line

1992 ◽  
Vol 12 (4) ◽  
pp. 1864-1871
Author(s):  
G Q Daley ◽  
R A Van Etten ◽  
P K Jackson ◽  
A Bernards ◽  
D Baltimore
Keyword(s):  
Plasma Membrane ◽  
Cell Line ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Hematopoietic Cell ◽  
Myelogenous Leukemia ◽  
3T3 Fibroblasts ◽  
Nih 3T3

N-terminal myristoylation can promote the association of proteins with the plasma membrane, a property that is required for oncogenic variants of Src and Abl to transform fibroblastic cell types. The P210bcr/abl protein of chronic myelogenous leukemia cells is not myristoylated and does not stably transform NIH 3T3 fibroblasts; however, it will transform lymphoid and myeloid cell types in vitro and in vivo, suggesting that myristoylation is not required for Abl variants to transform hematopoietic cells. To test this hypothesis, we introduced point mutations that disrupt myristoylation into two activated Abl proteins, v-Abl and a deletion mutant of c-Abl (delta XB), and examined their ability to transform an interleukin-3-dependent lymphoblastoid cell line, Ba/F3. Neither of the nonmyristoylated Abl proteins transformed NIH 3T3 fibroblasts, but like P210bcr/abl, both were capable of transforming the Ba/F3 cells to factor independence and tumorigenicity. Nonmyristoylated Abl variants did not associate with the plasma membrane in the transformed Ba/F3 cells. These results demonstrate that Abl proteins can transform hematopoietic cells in the absence of membrane association and suggest that distinct functions of Abl are required for transformation of fibroblast and hematopoietic cell types.

Freeze-substitution of rye grass and ragweed pollen grains

1990 ◽  
Vol 48 (3) ◽  
pp. 686-687
Author(s):  
Liza B. Martinez ◽  
Susan M. Wick
Keyword(s):  
Cell Function ◽  
Pollen Grains ◽  
Freeze Substitution ◽  
Cell Types ◽  
Rapid Freezing ◽  
Rye Grass ◽  
Acrylic Resins ◽  
Allergenic Proteins ◽  
Cold Embedding ◽  
Structural Preservation

Rapid freezing and freeze-substitution have been employed as alternatives to chemical fixation because of the improved structural preservation obtained in various cell types. This has been attributed to biomolecular immobilization derived from the extremely rapid arrest of cell function. These methods allow the elimination of conventionally used fixatives, which may have denaturing or “masking” effects on proteins. Thus, this makes them ideal techniques for immunocytochemistry, in which preservation of both ultrastructure and antigenicity are important. These procedures are also compatible with cold embedding acrylic resins which are known to increase sensitivity in immunolabelling.This study reveals how rapid freezing and freeze-substitution may prove to be useful in the study of the mobile allergenic proteins of rye grass and ragweed. Most studies have relied on the use of osmium tetroxide to achieve the necessary ultrastructural detail in pollen whereas those that omitted it have had to contend with poor overall preservation.

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