p(FPLX:PKA)

Entity

Name

PKA

Namespace

FPLX

Namespace Version

20180917

Namespace URL

https://raw.githubusercontent.com/sorgerlab/famplex/e8ae9926ff95266032cb74f77973c84939bffbeb/export/famplex.belns

An ever-growing body of evidence indicates that in CNS and parasympathetic nervous system neurons and in heterologous systems expressing specific nAChR subtypes, nicotine stimulates several Ca2+-dependent kinases, including PI3K, protein kinase C (PKC), protein kinase A (PKA), calmodulin-dependent protein kinase II (CAM kinase II), and extracellular signal-regulated kinases (ERKs; Refs. 108, 112, 146, 318, 469). PubMed:19126755

Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 . PubMed:30116051

Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin PubMed:26692334

PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance. PubMed:26692334

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

During the induction of long-term facilitation in the snail, the regulatory subunit of cAMP-dependent protein kinase (PKA) is ubiquitinated and degraded by the proteasome, generating persistently activated PKA (Hegde et al. 1993). PubMed:22908190

PKA is a known substrate of Syk, and it has been shown that Syk inhibits PKA activity by phosphorylating Tyr-330 of the PKA catalytic subunit (60), further supporting our observation. PubMed:25331948

We found that Syk inhibition with BAY61-3606 induced CREB phosphorylation, although that event is inhibited in the presence of a selective PKA inhibitor (Fig. 10, A and B) further showing that Syk inhibition results in PKA activation. PubMed:25331948

PKA is a known substrate of Syk, and it has been shown that Syk inhibits PKA activity by phosphorylating Tyr-330 of the PKA catalytic subunit (60), further supporting our observation. PubMed:25331948

It has been demonstrated that phosphorylation of nicotinic receptors by protein kinase A, protein kinase C, and tyrosine kinase can regulate receptor activity PubMed:26813123

Chronic administration of CGS-21680, a selective agonist of the AC-coupled adenosine A 2A receptor, restored proteasomal activity in cellular and murine models for HD via PKA-mediated Ser120 phosphorylation of the RPT6 component of the 19S subunit 231 . PubMed:30116051

A further potent detaching site is phosphoS214, which can be phosphorylated by PKA and other kinases of the AGC group (PKA/PKG/PKC group of protein kinases), and is up-regulated during mitosis (16, 63). Tau contains one or two cysteines in the repeat domain (C291 in R2, present in 4R isoforms, and C322 in R3), which can be engaged in intra- or intermolecular cross-linking affecting conformation, dimerization and aggregation (108). PubMed:17493042

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. PubMed:17078951

Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). PubMed:23001711

Rolipram is a specific phosphodiesterase type 4 (PDE4) inhibitor that increases cAMP levels in multiple tissues in vivo. The chymotrypsin-like activity of the 26S proteasomes in crude extracts was elevated after administration of db-cAMP or rolipram but was blocked by epoxomicin PubMed:26692334

PKA stimulation attenuated proteasome dysfunction, probably through proteasome subunit phosphorylation resulting in lower levels of aggregated tau and improvements in cognitive performance. PubMed:26692334

Adding another layer of complexity to the regulation of PP2A holoenzymes, protein kinase A-mediated serine phosphorylation of selective PPP2R5A and PPP2R5D regulatory subunits belonging to the B’family can also modulate PP2A catalytic activity (Ahn et al.,2007; Kirchhefer et al.,2014). PubMed:24653673

Adding another layer of complexity to the regulation of PP2A holoenzymes, protein kinase A-mediated serine phosphorylation of selective PPP2R5A and PPP2R5D regulatory subunits belonging to the B’family can also modulate PP2A catalytic activity (Ahn et al.,2007; Kirchhefer et al.,2014). PubMed:24653673

Other serine and threonine residues, not followed by proline, are phosphorylated by other protein kinases, including microtubule-affinity-regulating kinase (MARK) (Drewes et al., 1993), calcium/ calmodulin kinase II (CAMKII), cAMP-dependent kinase (PKA) (Johnson et al., 1992), and casein kinase II (Greenwood et al., 1994). PubMed:12428809

Activated PKA induces transcription of ApUCH (UCH-L1 in mammals), a deubiquitinating enzyzme, which has been found to be critical for the induction of long-term facilitation (Hegde et al. 1997). PubMed:22908190

GSK3β phosphorylation at Ser-9 has been shown to be mediated by PKA and AKT (protein kinase B) (57, 58). PubMed:25331948

We found that KT5270 effectively suppressed GSK3β phosphorylation at Ser-9 induced by BAY61-3606 (Fig. 10B) suggesting that this event is mediated by an activation of PKA. PubMed:25331948

We found that Syk inhibition with BAY61-3606 induced CREB phosphorylation, although that event is inhibited in the presence of a selective PKA inhibitor (Fig. 10, A and B) further showing that Syk inhibition results in PKA activation. PubMed:25331948

The responsible kinases include 1) proline-directed protein kinases (PDPKs) targeting SP or TP motifs [e.g., GSK3b, cyclindependent kinase (CDK)-5, and MAPKs]; 2) non–proline directed protein kinases targeting KXGS-motifs [e.g., PKA, microtubule affinity-regulating kinase and synapses of the amphid defective (SADK)]; 3) protein kinases specific for tyrosines (e.g., Src, Lck, Syk, Fyn, and c-Abl kinase) (91). PubMed:29191965

Other phosphorylation sites in or near the repeat domain are phosphorylated by microtubule affinity-regulating kinases (MARKs; also known as PAR1 kinases), cyclic AMP-dependent protein kinase (PKA) and Ca2+- or calmodulin-dependent protein kinase II (CaMKII), among others PubMed:26631930

For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules PubMed:26631930