scholarly journals Potential Agents against Plasma Leakage

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Jeanne Adiwinata Pawitan
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion ◽  
Rho Gtpases ◽  
Deleterious Effect ◽  
Bacterial Infections ◽  
Severe Dengue ◽  
Caveolin 1 ◽  
Plasma Leakage ◽  
Angiopoetin 1 ◽  
Kinase A

Shock due to severe plasma leakage may happen in infectious diseases such as severe dengue and sepsis due to various bacterial infections, which may be deleterious and may lead to death. Various substances and proteins are known to modulate the effects of proleakage mediators and counteract the deleterious effect of plasma leakage. Some of the various substances and proteins such as focal adhesion kinase (FAK), the Rho GTPases, protein kinase A, and caveolin-1 have dual actions; therefore they are not suitable for therapy. However, sphingosine 1phosphate and its receptor agonists, Angiopoetin-1, Slit, and Bbeta15–42 may be promising.

scholarly journals Identification of integrin-stimulated sites of serine phosphorylation in FRNK, the separately expressed C-terminal domain of focal adhesion kinase: a potential role for protein kinase A

1997 ◽  
Vol 324 (1) ◽  
pp. 141-149 ◽  
Author(s):  
Alan RICHARDSON ◽  
John D. SHANNON ◽  
Reid B. ADAMS ◽  
Michael D. SCHALLER ◽  
J. Thomas PARSONS
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Focal Adhesion Kinase ◽  
Tyrosine Phosphorylation ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Cell Spreading ◽  
Serine Phosphorylation ◽  
Early Event ◽  
Kinase A

Focal adhesion kinase (pp125FAK) is a protein tyrosine kinase that is localized to focal adhesions in many cell types and which undergoes tyrosine phosphorylation after integrin binding to extracellular matrix. In some cells the C-terminal non-catalytic domain of pp125FAK is expressed as a separate protein referred to as FRNK (FAK-related, non-kinase). We have previously shown that overexpression of FRNK inhibits tyrosine phosphorylation of pp125FAK and its substrates as well as inhibiting cell spreading on fibronectin. In this report we identify Ser148 and Ser151 as residues in FRNK that are phosphorylated after tyrosine phosphorylation of pp125FAK and in response to integrin binding to fibronectin. Tyrosine phosphorylation of pp125FAK appears to be an early event after integrin occupancy, and serine phosphorylation of FRNK occurs significantly later. Treatment of fibroblasts with a series of protein kinase A inhibitors delayed serine phosphorylation of FRNK as well as cell spreading on fibronectin and tyrosine phosphorylation of pp125FAK. However, these PKA inhibitors are unlikely to delay cell spreading simply by preventing serine phosphorylation of FRNK, as overexpression of FRNK containing mutations of Ser148 and Ser151 either singly or jointly to either alanine or glutamate residues did not significantly alter the ability of FRNK to act as an inhibitor of pp125FAK.

scholarly journals Protein kinase A-dependent increase in WAVE2 expression induced by the focal adhesion protein vinexin

2006 ◽  
Vol 11 (3) ◽  
pp. 281-292 ◽  
Author(s):  
Masaru Mitsushima ◽  
Takuhito Sezaki ◽  
Rie Akahane ◽  
Kazumitsu Ueda ◽  
Shiro Suetsugu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Focal Adhesion ◽  
Adhesion Protein ◽  
Focal Adhesion Protein ◽  
Kinase A

scholarly journals CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

2017 ◽  
Vol 37 (14) ◽  
Author(s):  
Kyoung-Jin Lee ◽  
Yuri Kim ◽  
Yeon Ho Yoo ◽  
Min-Seo Kim ◽  
Sun-Hee Lee ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Focal Adhesion Kinase ◽  
Signaling Pathway ◽  
Focal Adhesion ◽  
Transmembrane Protein ◽  
Β1 Integrin ◽  
Agonist Ligands ◽  
Kinase A

ABSTRACT The human CD99 protein is a 32-kDa glycosylated transmembrane protein that regulates various cellular responses, including cell adhesion and leukocyte extravasation. We previously reported that CD99 activation suppresses β1 integrin activity through dephosphorylation of focal adhesion kinase (FAK) at Y397. We explored a molecular mechanism underlying the suppression of β1 integrin activity by CD99 agonists and its relevance to tumor growth in vivo. CD99-Fc fusion proteins or a series of CD99-derived peptides suppressed β1 integrin activity by specifically interacting with three conserved motifs of the CD99 extracellular domain. CD99CRIII3, a representative CD99-derived 3-mer peptide, facilitated protein kinase A-SHP2 interaction and subsequent activation of the HRAS/RAF1/MEK/ERK signaling pathway. Subsequently, CD99CRIII3 induced FAK phosphorylation at S910, which led to the recruitment of PTPN12 and PIN1 to FAK, followed by FAK dephosphorylation at Y397. Taken together, these results indicate that CD99-derived agonist ligands inhibit fibronectin-mediated β1 integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway.

Two distinct caveolin-1 domains mediate the functional interaction of caveolin-1 with protein kinase A

2001 ◽  
Vol 281 (4) ◽  
pp. C1241-C1250 ◽  
Author(s):  
Babak Razani ◽  
Michael P. Lisanti
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Mutational Analysis ◽  
Dominant Negative ◽  
Wild Type ◽  
Functional Interaction ◽  
Caveolin 1 ◽  
Kinase A

Numerous components of the cAMP-based signaling cascade, namely G-proteins and G- protein coupled receptors, adenylyl cyclase, and protein kinase A (PKA) have been localized to caveolae and shown to be regulated by the caveolar marker proteins, the caveolins. In order to gain mechanistic insights into these processes in vivo, we have assessed the functional interaction of caveolin-1 (Cav-1) with PKA using mutational analysis. As two regions of Cav-1 had previously been implicated in PKA signaling in vitro, we constructed Cav-1 molecules with mutations/deletions in one or both of these domains. Examination of these mutants shows that Cav-1 requires the presence of either the scaffolding domain or the COOH-terminal domain (but not both) to functionally interact with and inhibit PKA. Interestingly, in contrast to the wild-type protein, these Cav-1 mutants are not localized to caveolae microdomains. However, upon coexpression with wild-type Cav-1, a substantial amount of the mutants was recruited to the caveolae membrane fraction. Using the Cav-1 double mutant with both disrupted scaffolding and COOH-terminal domains, we show that wild-type Cav-1's inhibition of PKA signaling can be partially abrogated in a dose-responsive manner; i.e., the mutant acts in a dominant-negative fashion. Thus, this dominant-negative caveolin-1 mutant will be extremely valuable for assessing the functional role of endogenous caveolin-1 in regulating a variety of other signaling cascades.

Mechanisms of ionomycin-induced endothelial cell barrier dysfunction

1997 ◽  
Vol 273 (1) ◽  
pp. L172-L184 ◽  
Author(s):  
J. G. Garcia ◽  
K. L. Schaphorst ◽  
S. Shi ◽  
A. D. Verin ◽  
C. M. Hart ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinase A ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Cell Permeability ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Kinase A

Myosin light chain (MLC) phosphorylation catalyzed by the Ca(2+)- calmodulin-dependent MLC kinase (MLCK) is critical to thrombin-mediated endothelial cell gap formation and barrier dysfunction. We have tested the hypothesis that the Ca2+ ionophore ionomycin stimulates MLCK-dependent endothelial cell contraction and permeability. Ionomycin significantly increased albumin clearance and decreased electrical resistance across confluent bovine pulmonary microvascular and macrovascular endothelial cell monolayers in a concentration-dependent manner that was temporally similar to that produced by thrombin. In contrast, however, ionomycin produced a significant Ca(2+)-dependent reduction in the levels of phosphorylated MLC with evidence of serine/threonine phosphatase activation. Potential MLCK-independent mechanisms of endothelial cell permeability were examined with little evidence to support a role for stimulated nitric oxide synthase or phospholipase A2 activities. Importantly, ionomycin produced 1) reductions in the activities of the barrier protective adenylate cyclase and the adenosine 3',5'-cyclic monophosphate-dependent protein kinase A, 2) dramatic dose- and time-dependent inhibition of endothelial cell tyrosine kinase activities, and 3) marked decreases in the phosphotyrosine content of the p125 focal adhesion kinase. These data indicate that ionomycin produces endothelial cell barrier dysfunction by mechanisms that are independent of MLCK activation and may involve reductions in endothelial cell tethering forces via inhibition of protein kinase A and tyrosine kinase activities, especially the p125 focal adhesion kinase.

scholarly journals Phosphorylation of STEF/Tiam2 by protein kinase A is critical for Rac1 activation and neurite outgrowth in dibutyryl cAMP–treated PC12D cells

2011 ◽  
Vol 22 (10) ◽  
pp. 1780-1790 ◽  
Author(s):  
Akihiro Goto ◽  
Mikio Hoshino ◽  
Michiyuki Matsuda ◽  
Takeshi Nakamura
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Neurite Outgrowth ◽  
Rho Gtpases ◽  
Critical Role ◽  
Resonance Energy ◽  
Axon Growth ◽  
Dibutyryl Camp ◽  
Neuronal Morphogenesis ◽  
Kinase A

The second messenger cAMP plays a pivotal role in neurite/axon growth and guidance, but its downstream pathways leading to the regulation of Rho GTPases, centrally implicated in neuronal morphogenesis, remain elusive. We examined spatiotemporal changes in Rac1 and Cdc42 activity and phosphatidylinositol 3,4,5-triphosphate (PIP3) concentration in dibutyryl cAMP (dbcAMP)-treated PC12D cells using Förster resonance energy transfer–based biosensors. During a 30-min incubation with dbcAMP, Rac1 activity gradually increased throughout the cells and remained at its maximal level. There was no change in PIP3 concentration. After a 5-h incubation with dbcAMP, Rac1 and Cdc42 were activated at the protruding tips of neurites without PIP3 accumulation. dbcAMP-induced Rac1 activation was principally mediated by protein kinase A (PKA) and Sif- and Tiam1-like exchange factor (STEF)/Tiam2. STEF depletion drastically reduced dbcAMP-induced neurite outgrowth. PKA phosphorylates STEF at three residues (Thr-749, Ser-782, Ser-1562); Thr-749 phosphorylation was critical for dbcAMP-induced Rac1 activation and neurite extension. During dbcAMP-induced neurite outgrowth, PKA activation at the plasma membrane became localized to neurite tips; this localization may contribute to local Rac1 activation at the same neurite tips. Considering the critical role of Rac1 in neuronal morphogenesis, the PKA—STEF–Rac1 pathway may play a crucial role in cytoskeletal regulation during neurite/axon outgrowth and guidance, which depend on cAMP signals.

Early signalling events of autophagy

2013 ◽  
Vol 55 ◽  
pp. 1-15 ◽  
Author(s):  
Laura E. Gallagher ◽  
Edmond Y.W. Chan
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Interacting Protein ◽  
The Core ◽  
Autophagy Gene ◽  
Autophagy Induction ◽  
Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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