Regulation of inhibitory neurotransmission by the scaffolding protein ankyrin repeat-rich membrane spanning/kinase D-interacting substrate of 220 kDa

2010 ◽  
Vol 88 (16) ◽  
pp. 3447-3456 ◽  
Author(s):  
Jhon-Jairo Sutachan ◽  
Moses V. Chao ◽  
Ipe Ninan
Keyword(s):  
Ankyrin Repeat ◽  
Scaffolding Protein ◽  
Inhibitory Neurotransmission ◽  
Membrane Spanning

scholarly journals Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Katie Pollock ◽  
Manjuan Liu ◽  
Mariola Zaleska ◽  
Mirco Meniconi ◽  
Mark Pfuhl ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Substrate Binding ◽  
Ankyrin Repeat ◽  
Telomere Maintenance ◽  
Scaffolding Protein ◽  
Cellular Functions ◽  
Wide Range ◽  
Differential Scanning Fluorimetry ◽  
Potential Alternative ◽  
Hippo Signalling

AbstractThe PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signalling, Hippo signalling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening programme against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) spectroscopy. We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.

Ankyrin repeat-rich membrane spanning/Kidins220 protein interacts with mammalian Septin 5

2010 ◽  
Vol 30 (2) ◽  
pp. 143-148 ◽  
Author(s):  
Han Jeong Park ◽  
Hwan-Woo Park ◽  
Shin-Jae Lee ◽  
Juan Carlos Arevalo ◽  
Young-Seok Park ◽  
...  
Keyword(s):  
Ankyrin Repeat ◽  
Membrane Spanning

scholarly journals Upregulated ankyrin repeat-rich membrane spanning protein contributes to tumour progression in cutaneous melanoma

2011 ◽  
Vol 104 (6) ◽  
pp. 982-988 ◽  
Author(s):  
Y H Liao ◽  
S M Hsu ◽  
H L Yang ◽  
M S Tsai ◽  
P H Huang
Keyword(s):  
Cutaneous Melanoma ◽  
Tumour Progression ◽  
Ankyrin Repeat ◽  
Membrane Spanning

scholarly journals Ankyrin Repeat-Rich Membrane Spanning Protein (Kidins220) Is Required for Neurotrophin and Ephrin Receptor-Dependent Dendrite Development

2012 ◽  
Vol 32 (24) ◽  
pp. 8263-8269 ◽  
Author(s):  
Y. Chen ◽  
W.-Y. Fu ◽  
J. P. K. Ip ◽  
T. Ye ◽  
A. K. Y. Fu ◽  
...  
Keyword(s):  
Ankyrin Repeat ◽  
Dendrite Development ◽  
Ephrin Receptor ◽  
Membrane Spanning

scholarly journals The Ankyrin Repeat-rich Membrane Spanning (ARMS)/Kidins220 Scaffold Protein Is Regulated by Activity-dependent Calpain Proteolysis and Modulates Synaptic Plasticity

2010 ◽  
Vol 285 (52) ◽  
pp. 40472-40478 ◽  
Author(s):  
Synphen H. Wu ◽  
Juan Carlos Arévalo ◽  
Veronika E. Neubrand ◽  
Hong Zhang ◽  
Ottavio Arancio ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Scaffold Protein ◽  
Ankyrin Repeat ◽  
Membrane Spanning ◽  
Activity Dependent

scholarly journals Ankyrin Repeat-rich Membrane Spanning/Kidins220 protein regulates dendritic branching and spine stabilityin vivo

2009 ◽  
Vol 69 (9) ◽  
pp. 547-557 ◽  
Author(s):  
Synphen H. Wu ◽  
Juan Carlos Arévalo ◽  
Federica Sarti ◽  
Lino Tessarollo ◽  
Wen-Biao Gan ◽  
...  
Keyword(s):  
Ankyrin Repeat ◽  
Dendritic Branching ◽  
Membrane Spanning

scholarly journals Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase

2019 ◽  
Author(s):  
Katie Pollock ◽  
Manjuan Liu ◽  
Mariola Zaleska ◽  
Mark Pfuhl ◽  
Ian Collins ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Screening Program ◽  
Substrate Binding ◽  
Ankyrin Repeat ◽  
Telomere Maintenance ◽  
Scaffolding Protein ◽  
Cellular Functions ◽  
Wide Range ◽  
Differential Scanning Fluorimetry ◽  
Potential Alternative

AbstractThe PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signaling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR). We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.

SHCA PHOSPHOTYROSINE DERIVED SIGNALING IS REQUIRED FOR THE MAINTENANCE OF CARDIAC FUNCTION

2008 ◽  
Vol 31 (4) ◽  
pp. 23
Author(s):  
Rachel Vanderlaan ◽  
Rod Hardy ◽  
Golam Kabir ◽  
Peter Back ◽  
A J Pawson
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Function ◽  
Tyrosine Kinases ◽  
Sh2 Domain ◽  
Scaffolding Protein ◽  
Restricted Domain ◽  
Downstream Signaling ◽  
Matrix Interactions ◽  
Extracellular Matrix Interactions ◽  
Ptb Domain

Background: ShcA, a scaffolding protein, generates signalspecificity by docking to activated tyrosine kinases through distinct phosphotyrosine recognition motifs, while mediating signal complexity through formation of diverse downstream phosphotyrosine complexes. Mammalian ShcA encodes 3 isoforms having a modular architecture of a PTB domain and SH2 domain, separated by a CH1 region containing tyrosine phosphorylation sites important in Ras-MAPK activation. Objective and Methods: ShcA has a necessary role in cardiovascular development^1,2. However, the role of ShcA in the adult myocardium is largely unknown, also unclear, is how ShcA uses its signaling modules to mediate downstream signaling. To this end, cre/loxP technology was employed to generate a conditional ShcA allele series. The myocardial specific ShcA KO (ShcA CKO) and myocardial restricted domain mutant KI mice were generated using cre expressed from the mlc2v locus^3 coupled with the ShcA floxed allele and in combination with the individual ShcA domain mutant KI alleles^2. Results: ShcACKO mice develop a dilated cardiomyopathy phenotype by 3 months of life, typified by depressed cardiac function and enlarged chamber dimensions. Isolated cardiomyocytes from ShcA CKO mice have preserved contractility indicating an uncoupling between global heart function and single myocyte contractile mechanics. Force-length experiments suggest that the loss of shcAmediates the uncoupling through deregulation of extracellular matrix interactions. Subsequent, analysis of the ShcA myocardial restricted domain mutant KImice suggests that ShcA requires PTB domain docking to upstream tyrosine kinases and subsequent phosphorylation of the CH1 tyrosines important for downstream signaling. Conclusion: ShcA is required for proper maintenance of cardiac function, possibly regulation of extracellular matrix interactions. References: 1. Lai KV, Pawson AJ. The ShcA phosphotyrosine docking protein sensitizescardiovascular signaling in the mouse embryo. Genes and Dev 2000;14:1132-45. 2. Hardy WR. et al. Combinatorial ShcA docking interactions supportdiversity in tissue morphogenesis. Science2007;317:251-6. 3.Minamisawa, s. et al. A post-transcriptional compensatory pathway inheterozygous ventricular myosin light chain 2-deficient mice results in lack ofgene dosage effect during normal cardiac growth or hypertrophy. J Biol Chem 1999;274:10066-70.

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