Role of tyrosine kinases in lymphocyte activation: Targets for drug intervention

Hanke, J H; Pollok, Brian A.; Changelian, Paul S.

doi:10.1007/bf01797862

Cited by 21 publications

(16 citation statements)

References 184 publications

(195 reference statements)

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“…PP2 is a widely used specific and effective SFK inhibitor [63]. PP2 binds between the two lobes of the kinase domain and prevents usual SRC substrates from binding [64].…”

Section: Discussionmentioning

confidence: 99%

Ouabain Stimulates a Na+/K+-ATPase-Mediated SFK-Activated Signalling Pathway That Regulates Tight Junction Function in the Mouse Blastocyst

2011

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The Na+/K+-ATPase plays a pivotal role during preimplantation development; it establishes a trans-epithelial ionic gradient that facilitates the formation of the fluid-filled blastocyst cavity, crucial for implantation and successful pregnancy. The Na+/K+-ATPase is also implicated in regulating tight junctions and cardiotonic steroid (CTS)-induced signal transduction via SRC. We investigated the expression of SRC family kinase (SFK) members, Src and Yes, during preimplantation development and determined whether SFK activity is required for blastocyst formation. Embryos were collected following super-ovulation of CD1 or MF1 female mice. RT-PCR was used to detect SFK mRNAs encoding Src and Yes throughout preimplantation development. SRC and YES protein were localized throughout preimplantation development. Treatment of mouse morulae with the SFK inhibitors PP2 and SU6656 for 18 hours resulted in a reversible blockade of progression to the blastocyst stage. Blastocysts treated with 10−3 M ouabain for 2 or 10 minutes and immediately immunostained for phosphorylation at SRC tyr418 displayed reduced phosphorylation while in contrast blastocysts treated with 10−4 M displayed increased tyr418 fluorescence. SFK inhibition increased and SFK activation reduced trophectoderm tight junction permeability in blastocysts. The results demonstrate that SFKs are expressed during preimplantation development and that SFK activity is required for blastocyst formation and is an important mediator of trophectoderm tight junction permeability.

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“…PP2 is a widely used specific and effective SFK inhibitor [63]. PP2 binds between the two lobes of the kinase domain and prevents usual SRC substrates from binding [64].…”

Section: Discussionmentioning

confidence: 99%

Ouabain Stimulates a Na+/K+-ATPase-Mediated SFK-Activated Signalling Pathway That Regulates Tight Junction Function in the Mouse Blastocyst

2011

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“…pyrimidin-4-amine (PP2) (10 µM, 30 minutes), a potent and specific pharmacological inhibitor of SFK's kinase catalytic activity (Hanke et al, 1995;Jin et al, 2017;Tomatis et al, 2013). We used the structurally related inactive analogue 1-phenyl-1H-pyrazolo[3 (Bain et al, 2003).…”

Section: The Catalytic Activity Of Fyn Does Not Alter the Nanoscale Omentioning

confidence: 99%

Frontotemporal dementia mutant tau (P301L) locks Fyn in an open, active conformation conducive to nanoclustering

Small

Martínez-Mármol

Wallis

et al. 2020

Preprint

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Fyn is a Src kinase that controls critical signalling cascades and its postsynaptic enrichment underpins synaptotoxicity in Alzheimer's disease (AD) and frontotemporal dementia (FTLD-tau). Previously, we found that pathogenic FTLD tau mutant (P301L) expression promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites via an unknown mechanism (Padmanabhan et al., 2019). Here, we imaged Fyn-mEos2 using single particle tracking photoactivated localization microscopy (sptPALM) to demonstrate that nanoclustering of Fyn in hippocampal dendrites is promoted by Fyn's open, primed conformation. Disrupting the auto-inhibitory, closed conformation of Fyn through phospho-inhibition, and perturbation of Fyn's SH3 domain increases, Fyn's nanoscale trapping. However, inhibition of Fyn's catalytic domain has no impact on its mobility. Tau-P301L promotes Fyn lateral trapping via Fyn opening and ensuing increased catalytic activation. Pathogenic tau may therefore drive synaptotoxicity by locking Fyn in an open, catalytically active conformation, leading to postsynaptic entrapment and aberrant signalling cascades.

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“…14 Pyrazolone derivatives are also possess antitubercular, anti-cancer, anti-HIV, anthelmintic and CNS activities. [16][17][18][19] The azo functionality, pyrazolone derivatives are important pharmacophoric functionalities which are present in various compounds which possess wide range of biological activities. Significance of benzofuran as a biopotent moiety, hence, an attempt to synthesize compounds which contain benzofuran moiety, azo functionality and pyrazolone ring system.…”

Section: Introductionmentioning

confidence: 99%

A short commentary on substituted Indoles, pyrazolones and imidazolinones

Asif¹,

Acharya²

2020

IJPCA

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Role of tyrosine kinases in lymphocyte activation: Targets for drug intervention

Cited by 21 publications

References 184 publications

Ouabain Stimulates a Na+/K+-ATPase-Mediated SFK-Activated Signalling Pathway That Regulates Tight Junction Function in the Mouse Blastocyst

Ouabain Stimulates a Na+/K+-ATPase-Mediated SFK-Activated Signalling Pathway That Regulates Tight Junction Function in the Mouse Blastocyst

Frontotemporal dementia mutant tau (P301L) locks Fyn in an open, active conformation conducive to nanoclustering

A short commentary on substituted Indoles, pyrazolones and imidazolinones

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