PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle

2005 ◽  
Vol 289 (2) ◽  
pp. E187-E196 ◽  
Author(s):  
Lily Q. Dong ◽  
Feng Liu
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
P38 Map Kinase ◽  
Activation Loop ◽  
Dependent Protein Kinase ◽  
Multiple Systems ◽  
Threonine Residue ◽  
Dependent Protein

Activation of members of the protein kinase AGC (cAMP dependent, cGMP dependent, and protein kinase C) family is regulated primarily by phosphorylation at two sites: a conserved threonine residue in the activation loop and a serine/threonine residue in a hydrophobic motif (HM) near the COOH terminus. Although phosphorylation of these kinases in the activation loop has been found to be mediated by phosphoinositide-dependent protein kinase-1 (PDK1), the kinase(s) that catalyzes AGC kinase phosphorylation in the HM remains uncharacterized. So far, at least 10 kinases have been suggested to function as an HM kinase or the so-called “PDK2,” including mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2), integrin-linked kinase (ILK), p38 MAP kinase, protein kinase Cα (PKCα), PKCβ, the NIMA-related kinase-6 (NEK6), the mammalian target of rapamycin (mTOR), the double-stranded DNA-dependent protein kinase (DNK-PK), and the ataxia telangiectasia mutated (ATM) gene product. However, whether any or all of these kinases act as a physiological HM kinase remains to be established. Nonetheless, available data suggest that multiple systems may be used in cells to regulate the activation of the AGC family kinases. It is possible that, unlike activation loop phosphorylation, phosphorylation of the HM site in the different AGC family kinases is mediated by distinct kinases. In addition, phosphorylation of the AGC family kinase at the HM site could be cell type, signaling pathway, and substrate specific. Identification and characterization of the bonafide HM kinase(s) will be essential to verify these hypotheses.

scholarly journals Diminished muscle growth in the obese Zucker rat following overload is associated with hyperphosphorylation of AMPK and dsRNA-dependent protein kinase

2012 ◽  
Vol 113 (3) ◽  
pp. 377-384 ◽  
Author(s):  
Anjaiah Katta ◽  
Sunil K. Kakarla ◽  
Nandini D. P. K. Manne ◽  
Miaozong Wu ◽  
Sudarsanam Kundla ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Muscle Growth ◽  
Mammalian Target Of Rapamycin ◽  
P38 Map Kinase ◽  
Initiation Factor ◽  
Dependent Protein Kinase ◽  
Insulin Resistant ◽  
Protein Ubiquitination ◽  
Dependent Protein ◽  
Inhibitor Of Protein Synthesis

Previous data have suggested that insulin-resistant skeletal muscle may exhibit a diminished ability to undergo hypertrophy and that this result may be mediated, at least in part, from decrements in mammalian target of rapamycin (mTOR) signaling (Katta A, Kundla S, Kakarla SK, Wu M, Fannin J, Paturi S, Liu H, Addagarla HS, Blough ER. Am J Physiol Regul Integr Comp Physiol 299: R1666–R1675, 2010). Herein, we attempt to extend these observations by determining if this attenuation in muscle growth is associated with alterations in AMP-activated protein kinase (AMPK) signaling, an upstream mediator of mTOR, and changes in the activation of dsRNA-dependent protein kinase (PKR), which functions as an inhibitor of protein synthesis and potential mediator of protein degradation. Compared with that observed in lean Zucker (LZ) rats, the phosphorylation of AMPKα at Thr172 was higher after 3 wk of overload in the insulin-resistant obese Zucker (OZ) soleus ( P < 0.05). This change in AMPKα phosphorylation was accompanied by increases in the amount of phosphorylated PKR (Thr446), elevations in the PKR-dependent phosphorylation of eukaryotic initiation factor (eIF)-2α (Ser51), augmented p38 MAP kinase (Thr180/Tyr182) phosphorylation, and increases in the amount of protein ubiquitination ( P < 0.05). Taken together, these results suggest that the diminished hypertrophic response we observe in the OZ rat may be mediated, at least in part, by the hyperactivation of AMPK- and PKR-related signaling.

Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 616-618 ◽  
Author(s):  
Antonija Jurak Begonja ◽  
Jörg Geiger ◽  
Natalia Rukoyatkina ◽  
Steffen Rauchfuss ◽  
Stepan Gambaryan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Thromboxane A2 ◽  
Human Platelets ◽  
P38 Map Kinase ◽  
Integrin Activation ◽  
Dependent Protein Kinase ◽  
Kinase Activation ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

Abstract p38 MAP kinase in human platelets is activated by platelet agonists including thrombin, thromboxane A2 (TxA2), ADP, and others. However, both upstream mechanisms of p38 MAP kinase activation, and their downstream sequelae, are presently controversial and essentially unclear. Certain studies report sequential activation of cGMP-dependent protein kinase (PKG) and p38/ERK pathways by platelet agonists, leading to integrin activation and secretion, whereas others establish an essential role of Src/ERK-mediated TxA2 generation for fibrinogen receptor activation in human platelets. Here, we show that ADP secreted from platelet-dense granules, and subsequent activation of P2Y12 receptors, as well as TxA2 release are important upstream mediators of p38 MAP kinase activation by thrombin. However, p38 MAP kinase activation did not significantly contribute to calcium mobilization, P-selectin expression, αIIbβ3 integrin activation, and aggregation of human platelets in response to thrombin. Finally, PKG activation did not stimulate, but rather inhibited, p38 MAP kinase in human platelets.

scholarly journals Genetic Involvement of a cAMP-Dependent Protein Kinase in a G Protein Signaling Pathway Regulating Morphological and Chemical Transitions in Aspergillus nidulans

Genetics ◽  
2001 ◽  
Vol 157 (2) ◽  
pp. 591-600
Author(s):  
Kiminori Shimizu ◽  
Nancy P Keller
Keyword(s):  
Protein Kinase ◽  
Aspergillus Nidulans ◽  
Signaling Pathway ◽  
G Protein ◽  
Radial Growth ◽  
Morphological Development ◽  
Dependent Protein Kinase ◽  
Α Subunit ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Abstract In the filamentous fungus Aspergillus nidulans, a heterotrimeric G protein α-subunit and an RGS domain protein, encoded by fadA and flbA, respectively, regulate production of the carcinogenic metabolite sterigmatocystin (ST) and asexual spores (i.e., conidia). We investigated the genetic involvement of the cAMP-dependent protein kinase catalytic subunit (PkaA), a potential downstream target of FadA activity, in ST production and conidiation. Relative to wild type, sporulation was decreased in the pkaA overexpression strain but was not totally absent, as occurs in ΔflbA or fadAG42R (fadA-dominant active) strains. Deletion of pkaA resulted in a hyper-conidiating strain with limited radial growth. This phenotype was epistatic to mutation in flbA or fadA; the double mutants ΔpkaA; ΔflbA and ΔpkaA; fadAG42R recovered sporulation and their radial growth was severely restricted. PkaA overexpression also negatively regulated AflR, the ST biosynthesis-specific transcription factor, both transcriptionally and post-transcriptionally. Deletion of pkaA restored ST production in the ΔflbA background but not in the fadAG42R background. These data provide genetic evidence that the FlbA/FadA signaling pathway regulating ST production and morphological development is partially mediated through PkaA.

scholarly journals The AGC Kinase SsAgc1 Regulates Sporisorium scitamineum Mating/Filamentation and Pathogenicity

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Yixu Wang ◽  
Yi Zhen Deng ◽  
Guobing Cui ◽  
Chengwei Huang ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Protein Kinases ◽  
Molecular Mechanisms ◽  
Economic Losses ◽  
Signal Molecules ◽  
Dependent Protein Kinase ◽  
Sporisorium Scitamineum ◽  
Fungal Mating ◽  
Dependent Protein

ABSTRACT Sporisorium scitamineum is the fungal pathogen causing severe sugarcane smut disease that leads to massive economic losses globally. S. scitamineum invades host cane by dikaryotic hyphae, formed after sexual mating of two haploid sporidia of opposite mating type. Therefore, mating/filamentation is critical for S. scitamineum pathogenicity, while its molecular mechanisms remain largely unknown. The AGC (cyclic AMP [cAMP]-dependent protein kinase 1 [protein kinase A {PKA}], cGMP-dependent protein kinase [PKG], and protein kinase C [PKC]) kinase family is a group of serine/threonine (Ser/Thr) protein kinases conserved among eukaryotic genomes, serving a variety of physiological functions, including cell growth, metabolism, differentiation, and cell death. In this study, we identified an AGC kinase, named SsAgc1 (for S. scitamineum Agc1), and characterized its function by reverse genetics. Our results showed that SsAgc1 is critical for S. scitamineum mating/filamentation and pathogenicity, and oxidative stress tolerance under some circumstances. Transcriptional profiling revealed that the SsAgc1 signaling pathway may control expression of the genes governing fungal mating/filamentation and tryptophan metabolism, especially for tryptophol production. We showed that tryptophan and tryptophol could at least partially restore ssagc1Δ mating/filamentation. Overall, our work revealed a signaling pathway mediated by AGC protein kinases to regulate fungal mating/filamentation, possibly through sensing and responding to tryptophol as signal molecules. IMPORTANCE The AGC signaling pathway represents a conserved distinct signaling pathway in regulation of fungal differentiation and virulence, while it has not been identified or characterized in the sugarcane smut fungus Sporisorium scitamineum. In this study, we identified a PAS domain-containing AGC kinase, SsAgc1, in S. scitamineum. Functional analysis revealed that SsAgc1 plays a regulatory role on the fungal dimorphic switch.

scholarly journals Stimulation of neuronal KATP channels by cGMP-dependent protein kinase: involvement of ROS and 5-hydroxydecanoate-sensitive factors in signal transduction

2010 ◽  
Vol 298 (4) ◽  
pp. C875-C892 ◽  
Author(s):  
Yongping Chai ◽  
Yu-Fung Lin
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Neuronal Excitability ◽  
Single Channel ◽  
Katp Channels ◽  
Membrane Excitability ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Stimulation Of

The ATP-sensitive potassium (KATP) channel couples intracellular metabolic state to membrane excitability. Recently, we demonstrated that neuronal KATP channels are functionally enhanced by activation of a nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) signaling cascade. In this study, we further investigated the intracellular mechanism underlying PKG stimulation of neuronal KATP channels. By performing single-channel recordings in transfected HEK293 and neuroblastoma SH-SY5Y cells, we found that the increase of Kir6.2/SUR1 (i.e., the neuronal-type KATP) channel currents by PKG activation in cell-attached patches was diminished by 5-hydroxydecanoate (5-HD), an inhibitor of the putative mitochondrial KATP channel; N-(2-mercaptopropionyl)glycine, a reactive oxygen species (ROS) scavenger, and catalase, a hydrogen peroxide (H2O2)-decomposing enzyme. These reagents also ablated NO-induced KATP channel stimulation and prevented the shifts in the single-channel open- and closed-time distributions resulting from PKG activation and NO induction. Bath application of H2O2 reproduced PKG stimulation of Kir6.2/SUR1 but did not activate tetrameric Kir6.2LRKR368/369/370/371AAAA channels. Moreover, neither the PKG activator nor exogenous H2O2 was able to enhance the function of KATP channels in the presence of Ca2+ chelators and calmodulin antagonists, whereas the stimulatory effect of H2O2 was unaffected by 5-HD. Altogether, in this report we provide novel evidence that activation of PKG stimulates neuronal KATP channels by modulating intrinsic channel gating via a 5-HD-sensitive factor(s)/ROS/Ca2+/calmodulin signaling pathway that requires the presence of the SUR1 subunit. This signaling pathway may contribute to neuroprotection against ischemic injury and regulation of neuronal excitability and neurotransmitter release by modulating the function of neuronal KATP channels.

scholarly journals Downregulation of cAMP-Dependent Protein Kinase Inhibitor-b Promotes Preeclampsia by Decreasing Phosphorylated Akt

2020 ◽  
Vol 28 (1) ◽  
pp. 178-185
Author(s):  
Chunfeng Liu ◽  
Hao Wang ◽  
Mo Yang ◽  
Yiheng Liang ◽  
Li Jiang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Matrix Metalloproteinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Dependent Protein Kinase ◽  
Phosphorylated Akt ◽  
Dependent Protein

AbstractPreeclampsia is a multi-system disease that is unique to human pregnancy. Impaired extravillous trophoblast migration and invasion accompanied by poor spiral vascular remodeling is thought to be the initial reason. This study investigated cAMP-dependent protein kinase inhibitor-b(PKIB) expression in placentas and its involvement in the pathogenesis of PE. We used immunohistochemistry and western blotting to calculate PKIB levels in the placentas. Then we knocked down PKIB by siRNA and used real-time cell analysis to assess the invasion and migration ability of trophoblasts. Tube formation assay and spheroid sprouting assay were utilized to identify the ability to form vessels of trophoblasts. At last, western blotting was used to demonstrate the level of phosphorylated Akt, as well as downstream-related genes of Akt signaling pathway in trophoblasts. We first found that PKIB expression level was lower in the PE placentas than in the normal placentas. In addition, we found that downregulation of PKIB can inhibit the migration, invasion, and the ability to form vessels of HTR8/SVneo cells. Downregulation of PKIB leaded to a decrease in phosphorylated Akt, as well as downstream proteins such as matrix metalloproteinase 2, matrix metalloproteinase 9, and glycogen synthase kinase 3β, which are related to migration and invasion. Our study revealed that the downregulation of PKIB expression resulted in decreased migration, invasion, and vessel formation ability by regulating Akt signaling pathway in placental trophoblasts in PE.

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