scholarly journals Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation

2003 ◽  
Vol 23 (11) ◽  
pp. 3884-3896 ◽  
Author(s):  
Keith Q. Tanis ◽  
Darren Veach ◽  
Henry S. Duewel ◽  
William G. Bornmann ◽  
Anthony J. Koleske
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Intramolecular Interactions ◽  
Activation Loop ◽  
Additive Effects ◽  
Nonreceptor Tyrosine Kinase ◽  
Kinase Activation ◽  
Surface Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stimulation Of

ABSTRACT The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

scholarly journals Rapid stimulation of mitogen-activated protein kinase of rat liver by prolactin

1994 ◽  
Vol 303 (2) ◽  
pp. 429-433 ◽  
Author(s):  
R Piccoletti ◽  
P Maroni ◽  
P Bendinelli ◽  
A Bernelli-Zazzera
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Female Rats ◽  
Protein Kinase Activity ◽  
Kinase Activation ◽  
Stimulation Of

Intraperitoneal prolactin administration to female rats caused a rapid and transient stimulation of hepatic mitogen-activated kinase (MAP kinase) activity measured in vitro as cytosolic phosphotransferase capacity towards two specific substrates. Myelin basic protein kinase activity of MAP kinase immunoprecipitates confirmed the specificity and magnified the prolactin effect. Immunoblot experiments with anti-(MAP kinase) and anti-phosphotyrosine antibodies showed changes in both electrophoretic mobility and phosphotyrosine content of 40 and 44 kDa isoenzymes suggesting that prolactin affects these isoforms. Concomitant with the increase in MAP kinase activity, prolactin induced tyrosine phosphorylation in a number of liver proteins, suggesting a rapid involvement of tyrosine kinases which might be correlated in some way with MAP kinase activation. Protein kinase C activity, which has been implicated in the regulation of MAP kinase and in mediating the prolactin effect, does not seem to participate in MAP kinase activation.

Cardioprotection involves activation of NF-κB via PKC-dependent tyrosine and serine phosphorylation of IκB-α

2003 ◽  
Vol 285 (4) ◽  
pp. H1753-H1758 ◽  
Author(s):  
Jun Zhang ◽  
Peipei Ping ◽  
Thomas M. Vondriska ◽  
Xian-Liang Tang ◽  
Guang-Wu Wang ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Coronary Occlusion ◽  
Kinase Inhibitor ◽  
Serine Phosphorylation ◽  
Inhibitory Protein ◽  
Nonreceptor Tyrosine Kinase ◽  
Pkc Inhibitor ◽  
Nonreceptor Tyrosine Kinases

Previous studies indicated that activation of PKC and Src tyrosine kinases by ischemic preconditioning (PC) may participate in the activation of NF-κB. However, the molecular mechanisms underlying activation of NF-κB during ischemic PC remain unknown. In the hearts of conscious rabbits, it was found that ischemic PC (6 cycles of 4-min coronary occlusion and 4-min reperfusion) significantly induced both tyrosine (+226.9 ± 42%) and serine (+137.0 ± 36%) phosphorylation of the NF-κB inhibitory protein IκB-α, concomitant with increased activation of the IκB-α kinases IKKα (+255.0 ± 46%) and IKKβ (+173.1 ± 35%). Furthermore, both tyrosine and serine phosphorylation of IκB-α were blocked by pretreatment with either the nonreceptor tyrosine kinase inhibitor lavendustin-A (LD-A) or the PKC inhibitor chelerythrine (Che) (both given at doses previously shown to block ischemic PC). Interestingly, Che completely abolished PC-induced activation of IKKα/β, whereas LD-A had no effect. In addition, IκB-α protein level did not change during ischemic PC. Together, these data indicate that ischemic PC-induced activation of NF-κB occurs through both tyrosine and serine phosphorylation of IκB-α and is regulated by nonreceptor tyrosine kinases and PKC.

scholarly journals Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis

2002 ◽  
Vol 157 (3) ◽  
pp. 521-532 ◽  
Author(s):  
Philipp Niethammer ◽  
Markus Delling ◽  
Vladimir Sytnyk ◽  
Alexander Dityatev ◽  
Kiyoko Fukami ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Lipid Raft ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Fgf Receptor ◽  
Nonreceptor Tyrosine Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Neural Cell Adhesion ◽  
Nonreceptor Tyrosine Kinases

The neural cell adhesion molecule (NCAM) has been reported to stimulate neuritogenesis either via nonreceptor tyrosine kinases or fibroblast growth factor (FGF) receptor. Here we show that lipid raft association of NCAM is crucial for activation of the nonreceptor tyrosine kinase pathway and induction of neurite outgrowth. Transfection of hippocampal neurons of NCAM-deficient mice revealed that of the three major NCAM isoforms only NCAM140 can act as a homophilic receptor that induces neurite outgrowth. Disruption of NCAM140 raft association either by mutation of NCAM140 palmitoylation sites or by lipid raft destruction attenuates activation of the tyrosine focal adhesion kinase and extracellular signal–regulated kinase 1/2, completely blocking neurite outgrowth. Likewise, NCAM-triggered neurite outgrowth is also completely blocked by a specific FGF receptor inhibitor, indicating that cosignaling via raft-associated kinases and FGF receptor is essential for neuritogenesis.

scholarly journals A phosphorylation of RIPK3 kinase initiates an intracellular apoptotic pathway that promotes corpus luteum regression

2021 ◽  
Author(s):  
Dianrong Li ◽  
Jie Chen ◽  
Jia Guo ◽  
Lin Li ◽  
Gaihong Cai ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Granulosa Cells ◽  
Kinase Activity ◽  
Caspase 8 ◽  
Activation Loop ◽  
Spontaneous Apoptosis ◽  
Apoptotic Pathway ◽  
Apoptosis Pathway ◽  
Luteal Regression ◽  
Kinase Activation

AbstractReceptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF2α induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF2α but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knockin mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.

scholarly journals Differential Activation of the Tyrosine Kinases ZAP-70 and Syk After FcγRI Stimulation

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 388-396 ◽  
Author(s):  
Naomi Taylor ◽  
Thomas Jahn ◽  
Susan Smith ◽  
Thomas Lamkin ◽  
Lisa Uribe ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Signal Transduction Pathway ◽  
Protein Tyrosine Kinases ◽  
Monocytic Cell ◽  
Monocytic Cells ◽  
Kinase Activation ◽  
Receptor Aggregation

Abstract Engagement of the high-affinity IgG Fc receptor (FcγRI) activates a signal transduction pathway involving tyrosine phosphorylation of associated kinases. We compared the activation of the related protein tyrosine kinases (PTKs), Syk and ZAP-70, in FcγRI-mediated signaling. Cross-linking of the FcγRI multimeric receptor in monocytic cells results in tyrosine phosphorylation of the FcεRIγ subunit and association of Syk with this complex. We stably introduced ZAP-70 via a retroviral vector into two monocytic cell lines, U937 and THP-1, which normally do not express ZAP-70. Neither Syk nor MAP kinase activation was affected by the presence of ZAP-70. Although transduced ZAP-70 had in vitro kinase activity and associated with FcεRIγ after receptor aggregation, it was not tyrosine phosphorylated. In contrast, both ZAP-70 and Syk were phosphorylated in a T-cell line in which their respective levels of expression were similar to those detected in U937/ZAP-70 cells. Therefore, these results suggest that requirements for Syk and ZAP-70 phosphorylation are distinct in a monocytic cell context.

scholarly journals Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 996-1002 ◽  
Author(s):  
Titus J. Boggon ◽  
Yiqun Li ◽  
Paul W. Manley ◽  
Michael J. Eck
Keyword(s):  
Crystal Structure ◽  
Tyrosine Kinases ◽  
Severe Combined Immunodeficiency ◽  
Kinase Domain ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Activation Loop ◽  
Gamma Chain ◽  
The Common ◽  
Nonreceptor Tyrosine Kinases

AbstractJak (Janus kinase) family nonreceptor tyrosine kinases are central mediators of cytokine signaling. The Jak kinases exhibit distinct cytokine receptor association profiles and so transduce different signals. Jak3 expression is limited to the immune system, where it plays a key role in signal transduction from cytokine receptors containing the common gamma-chain, γc. Patients unable to signal via γc present with severe combined immunodeficiency (SCID). The finding that Jak3 mutations result in SCID has made it a target for development of lymphocyte-specific immunosuppressants. Here, we present the crystal structure of the Jak3 kinase domain in complex with staurosporine analog AFN941. The kinase domain is in the active conformation, with both activation loop tyrosine residues phosphorylated. The phosphate group on pTyr981 in the activation loop is in part coordinated by an arginine residue in the regulatory C-helix, suggesting a direct mechanism by which the active position of the C-helix is induced by phosphorylation of the activation loop. Such a direct coupling has not been previously observed in tyrosine kinases and may be unique to Jak kinases. The crystal structure provides a detailed view of the Jak3 active site and will facilitate computational and structure-directed approaches to development of Jak3-specific inhibitors.

scholarly journals MuSK Kinase Activity is Modulated By A Serine Phosphorylation Site in The Kinase Loop

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
B. Z. Camurdanoglu ◽  
C. Hrovat ◽  
G. Dürnberger ◽  
M. Madalinski ◽  
K. Mechtler ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Cluster Size ◽  
Kinase Activity ◽  
Phosphorylation Site ◽  
Serine Phosphorylation ◽  
Activation Loop ◽  
Achr Cluster ◽  
Kinase Activation ◽  
Muscle Specific Kinase ◽  
Postsynaptic Differentiation

Abstract The neuromuscular junction (NMJ) forms when a motor neuron contacts a muscle fibre. A reciprocal exchange of signals initiates a cascade of signalling events that result in pre- and postsynaptic differentiation. At the centre of these signalling events stands muscle specific kinase (MuSK). MuSK activation, kinase activity and subsequent downstream signalling are crucial for NMJ formation as well as maintenance. Therefore MuSK kinase activity is tightly regulated to ensure proper NMJ development. We have identified a novel serine phosphorylation site at position 751 in MuSK that is increasingly phosphorylated upon agrin stimulation. S751 is also phosphorylated in muscle tissue and its phosphorylation depends on MuSK kinase activity. A phosphomimetic mutant of S751 increases MuSK kinase activity in response to non-saturating agrin concentrations . In addition, basal MuSK and AChR phosphorylation as well as AChR cluster size are increased. We believe that the phosphorylation of S751 provides a novel mechanism to relief the autoinhibition of the MuSK activation loop. Such a lower autoinhibition could foster or stabilize MuSK kinase activation, especially during stages when no or low level of agrin are present. Phosphorylation of S751 might therefore represent a novel mechanism to modulate MuSK kinase activity during prepatterning or NMJ maintenance.

scholarly journals Kinase Function of Brassinosteroid Receptor Specified by Two Allosterically Regulated Subdomains

2022 ◽  
Vol 12 ◽  
Author(s):  
Khawar Ali ◽  
Wenjuan Li ◽  
Yaopeng Qin ◽  
Shanshan Wang ◽  
Lijie Feng ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Kinase Activity ◽  
The Other ◽  
Activation Loop ◽  
Biological Functions ◽  
Kinase Activation ◽  
Downstream Signaling ◽  
Signaling Function ◽  
Insight Into

Plants acquire the ability to adapt to the environment using transmembrane receptor-like kinases (RLKs) to sense the challenges from their surroundings and respond appropriately. RLKs perceive a variety of ligands through their variable extracellular domains (ECDs) that activate the highly conserved intracellular kinase domains (KDs) to control distinct biological functions through a well-developed downstream signaling cascade. A new study has emerged that brassinosteroid-insensitive 1 (BRI1) family and excess microsporocytes 1 (EMS1) but not GASSHO1 (GSO1) and other RLKs control distinct biological functions through the same signaling pathway, raising a question how the signaling pathway represented by BRI1 is specified. Here, we confirm that BRI1-KD is not functionally replaceable by GSO1-KD since the chimeric BRI1-GSO1 cannot rescue bri1 mutants. We then identify two subdomains S1 and S2. BRI1 with its S1 and S2 substituted by that of GSO1 cannot rescue bri1 mutants. Conversely, chimeric BRI1-GSO1 with its S1 and S2 substituted by that of BRI1 can rescue bri1 mutants, suggesting that S1 and S2 are the sufficient requirements to specify the signaling function of BRI1. Consequently, all the other subdomains in the KD of BRI1 are functionally replaceable by that of GSO1 although the in vitro kinase activities vary after replacements, suggesting their functional robustness and mutational plasticity with diverse kinase activity. Interestingly, S1 contains αC-β4 loop as an allosteric hotspot and S2 includes kinase activation loop, proposedly regulating kinase activities. Further analysis reveals that this specific function requires β4 and β5 in addition to αC-β4 loop in S1. We, therefore, suggest that BRI1 specifies its kinase function through an allosteric regulation of these two subdomains to control its distinct biological functions, providing a new insight into the kinase evolution.

scholarly journals A novel nonreceptor tyrosine kinase, Srm: cloning and targeted disruption.

1994 ◽  
Vol 14 (10) ◽  
pp. 6915-6925 ◽  
Author(s):  
N Kohmura ◽  
T Yagi ◽  
Y Tomooka ◽  
M Oyanagi ◽  
R Kominami ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Structural Characteristics ◽  
Sequence Similarity ◽  
Embryonic Stem ◽  
Structural Features ◽  
Mutant Mice ◽  
Chromosome 2 ◽  
Nonreceptor Tyrosine Kinase ◽  
Nonreceptor Tyrosine Kinases

We have isolated a novel nonreceptor tyrosine kinase, Srm, that maps to the distal end of chromosome 2. It has SH2, SH2', and SH3 domains and a tyrosine residue for autophosphorylation in the kinase domain but lacks an N-terminal glycine for myristylation and a C-terminal tyrosine which, when phosphorylated, suppresses kinase activity. These are structural features of the recently identified Tec family of nonreceptor tyrosine kinases. The Srm N-terminal unique domain, however, lacks the structural characteristics of the Tec family kinases, and the sequence similarity is highest to Src in the SH region. The expression of two transcripts is rather ubiquitous and changes according to tissue and developmental stage. Mutant mice were generated by gene targeting in embryonic stem cells but displayed no apparent phenotype as in mutant mice expressing Src family kinases. These results suggest that Srm constitutes a new family of nonreceptor tyrosine kinases that may be redundant in function.

scholarly journals Ras and Rab interactor 1 controls neuronal plasticity by coordinating dendritic filopodial motility and AMPA receptor turnover

2017 ◽  
Vol 28 (2) ◽  
pp. 285-295 ◽  
Author(s):  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Carlos O. Oueslati Morales ◽  
Attila Ignácz ◽  
Anikó Erika Rátkai ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Neuronal Plasticity ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Critical Role ◽  
Surface Receptors ◽  
Chemically Induced ◽  
Cytoskeleton Remodeling ◽  
Knockout Animals ◽  
Nonreceptor Tyrosine Kinases

Ras and Rab interactor 1 (RIN1) is predominantly expressed in the nervous system. RIN1-knockout animals have deficits in latent inhibition and fear extinction in the amygdala, suggesting a critical role for RIN1 in preventing the persistence of unpleasant memories. At the molecular level, RIN1 signals through Rab5 GTPases that control endocytosis of cell-surface receptors and Abl nonreceptor tyrosine kinases that participate in actin cytoskeleton remodeling. Here we report that RIN1 controls the plasticity of cultured mouse hippocampal neurons. Our results show that RIN1 affects the morphology of dendritic protrusions and accelerates dendritic filopodial motility through an Abl kinase–dependent pathway. Lack of RIN1 results in enhanced mEPSC amplitudes, indicating an increase in surface AMPA receptor levels compared with wild-type neurons. We further provide evidence that the Rab5 GEF activity of RIN1 regulates surface GluA1 subunit endocytosis. Consequently loss of RIN1 blocks surface AMPA receptor down-regulation evoked by chemically induced long-term depression. Our findings indicate that RIN1 destabilizes synaptic connections and is a key player in postsynaptic AMPA receptor endocytosis, providing multiple ways of negatively regulating memory stabilization during neuronal plasticity.

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