Does Isoform Diversity Explain Functional Differences in the 14-3-3Protein Family?

Kjarland, E.; Keen, T J; Kleppe, Rune

doi:10.2174/138920106777549777

Cited by 60 publications

(40 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interaction of Rap1GAP2 and 14-3-3-All members for the 14-3-3 protein family are highly conserved and share high amino acid identity (30,31). With pulldown experiments we show that Rap1GAP2 binds to 14-3-3␤ and .…”

Section: Discussionmentioning

confidence: 84%

Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets

Hoffmeister

Riha

Neumüller

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

GTPase-activating proteins are required to terminate signaling by Rap1, a small guanine nucleotide-binding protein that controls integrin activity and cell adhesion. Recently, we identified Rap1GAP2, a GTPase-activating protein of Rap1 in platelets. Here we show that 14-3-3 proteins interact with phosphorylated serine 9 at the N terminus of Rap1GAP2. Platelet activation by ADP and thrombin enhances serine 9 phosphorylation and increases 14-3-3 binding to endogenous Rap1GAP2. Conversely, inhibition of platelets by endothelium-derived factors nitric oxide and prostacyclin disrupts 14-3-3 binding. These effects are mediated by cGMP-and cAMP-dependent protein kinases that phosphorylate Rap1GAP2 at serine 7, adjacent to the 14-3-3 binding site. 14-3-3 binding does not change the GTPase-activating function of Rap1GAP2 in vitro. However, 14-3-3 binding attenuates Rap1GAP2 mediated inhibition of cell adhesion. Our findings define a novel crossover point of activatory and inhibitory signaling pathways in platelets.Platelets are involved in many physiological and pathological events in the vascular system including hemostasis and thrombosis as well as inflammation, angiogenesis, and metastasis. Endothelium-derived messenger molecules nitric oxide (NO) and prostacyclin (PGI 2 ) 3 initiate two major inhibitory signaling pathways in platelets. NO and PGI 2 activate platelet guanylyl and adenylyl cyclases to produce cGMP and cAMP. In consequence cGMP and cAMP activate cGMP-and cAMP-dependent protein kinases (cGK/PKG and cAK/PKA) that phosphorylate substrate proteins leading to inhibition of platelet activation, adhesion and aggregation (1-3). To date only few substrates of cGK/cAKs in platelets have been characterized and the mechanisms mediating platelet inhibition downstream of the substrates are largely unknown. We and others (4, 5) have recently detected that cGK and cAK efficiently block agonistinduced formation of Rap1-GTP in platelets. Rap1 is a guanine nucleotide-binding protein that regulates integrin functions and plays a pivotal role in adhesion of many cell types (6 -9). In platelets Rap1 is required for adhesion, aggregation and thrombus formation (10). Because Rap1 controls integrin function and platelet aggregation, Rap1 inhibition might play a central role in platelet inhibition by NO and PGI 2 . Rap1 cycles between an active GTP-bound and an inactive GDP-bound conformation. The transition between these two states is controlled by unique guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP).In a previous study we identified Rap1GAP2, the only known GAP of Rap1 in platelets (11). Furthermore, in vitro experiments provided preliminary evidence for cGK-and cAK-mediated phosphorylation of Rap1GAP2 (11). Rap1GAP2 contains a central conserved GAP domain as well as large N-and C-terminal regions of unknown function. We hypothesized that these regions might be involved in protein/protein interactions and performed a genetic screening in yeast to identify Rap1GAP2-interacting proteins. In the p...

show abstract

Section: Discussionmentioning

confidence: 84%

Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets

Hoffmeister

Riha

Neumüller

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…14-3-3 (Ostrerova et al, 1999;Kleppe et al, 2001;Srivastava et al, 2002;Kjarland et al, 2006). Recently, Peng et al (2005) demonstrated that a functional interaction between ␣-synuclein and PP2A can regulate TH phosphorylation and TH activity.…”

Section: Discussionmentioning

confidence: 99%

“…In our recent study, we showed that ␣-synuclein interacts with PKC␦ and regulates its activity after neurotoxic insults (Kaul et al, 2005). Therefore, in the dopaminergic system, the physical and functional association between PKC␦, TH, and PP2A could be facilitated and/or regulated by chaperone proteins such as ␣-synuclein (Kaul et al, 2005;Peng et al, 2005) and14-3-3 (Ostrerova et al, 1999;Kleppe et al, 2001;Kjarland et al, 2006). Nevertheless, additional studies are required in both in vitro and in vivo model systems to elucidate the dynamics of physical and functional regulation of PKC␦ and PP2A in regulation of TH activity.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cδ Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons

Zhang¹,

Kanthasamy²,

Yang³

et al. 2007

J. Neurosci.

109

View full text Add to dashboard Cite

Tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, can be regulated by phosphorylation at multiple serine residues, including serine-40. In the present study, we report a novel interaction between a key member of the novel PKC family, protein kinase C␦ (PKC␦), and TH, in which the kinase modulates dopamine synthesis by negatively regulating TH activity via protein phosphatase 2A (PP2A). We observed that PKC␦ is highly expressed in nigral dopaminergic neurons and colocalizes with TH. Interestingly, suppression of PKC␦ activity with the kinase inhibitor rottlerin, PKC␦-small interfering RNA, or with PKC␦ dominant-negative mutant effectively increased a number of key biochemical events in the dopamine pathway, including TH-ser40 phosphorylation, TH enzymatic activity, and dopamine synthesis in neuronal cell culture models. Additionally, we found that PKC␦ not only physically associates with the PP2A catalytic subunit (PP2Ac) but also phosphorylates the phosphatase to increase its activity. Notably, inhibition of PKC␦ reduced the dephosphorylation activity of PP2A and thereby increased TH-ser40 phosphorylation, TH activity, and dopamine synthesis. To further validate our findings, we used the PKC␦ knock-out (PKC␦ Ϫ/Ϫ) mouse model. Consistent with other results, we found greater TH-ser40 phosphorylation and reduced PP2A activity in the substantia nigra of PKC␦ Ϫ/Ϫ mice than in wild-type mice. Importantly, this was accompanied by an increased dopamine level in the striatum of PKC␦Ϫ/Ϫ mice. Collectively, these results suggest that PKC␦ phosphorylates PP2Ac to enhance its activity and thereby reduces TH-ser40 phosphorylation and TH activity and ultimately dopamine synthesis.

show abstract

“…14-3-3 proteins are involved in a range of cellular processes including the regulation of enzyme activity, stimulation of protein-protein interactions, and the localization and function of ion channels. 93,94 ERretained GluK5 appears to be bound to COPI, whereas subunit assembly with GluK2 releases GluK5 from the ER and increases its interaction with 14-3-3ζ and subsequent surface expression 81 suggesting that the ER retention signals are masked following oligomerization and highlighting how correct receptor assembly can lead to the switching of interacting partners to regulate a trafficking checkpoint within the biosynthetic pathway.…”

Section: -3-3 Proteins and Copimentioning

confidence: 99%

Kainate receptor trafficking

González‐González

Konopacki

Rocca

et al. 2011

WIREs Membr Transp Signal

View full text Add to dashboard Cite

Kainate receptors (KARs) are ligand-gated ion channels that can regulate neuronal network activity and are involved in processes ranging from neuronal development and differentiation to neurodegeneration and neuronal cell death. They are tetrameric assemblies which can comprise different subunit combinations and are differentially targeted to specific cell surface compartments including preand postsynaptic membranes where they perform distinct functional roles. The processes regulating the constitutive and activity-dependent trafficking of KARs are subtle and complex. Intricate combinations of protein-protein interactions and post-translational modifications orchestrate their surface membrane delivery, residence time, internalization, and recycling or degradation. Furthermore, in addition to regulating surface expression, interacting proteins connect receptors to anchoring and signaling pathways. Although our knowledge of the processes that regulate KAR trafficking is far from complete, there has been significant progress toward defining the roles of many of these protein partners and post-translational modifications. 

show abstract

Does Isoform Diversity Explain Functional Differences in the 14-3-3Protein Family?

Cited by 60 publications

References 60 publications

Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets

Cyclic Nucleotide-dependent Protein Kinases Inhibit Binding of 14-3-3 to the GTPase-activating Protein Rap1GAP2 in Platelets

Protein Kinase Cδ Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons

Kainate receptor trafficking

Contact Info

Product

Resources

About