Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent

Meijer, Laurent; Thunnissen, A.M.W.H.; White, Alex William; Garnier, Matthieu; Nikolic, Margareta; Tsai, Li‐Huei; Walter, Jochen; Cleverley, Karen; Salinas, Patricia C.; Wu, Yong-Zhong; Biernat, Jacek; Mandelkow, Eva‐Maria; Kim, Sang Hoon; Pettit, George R.

doi:10.1016/s1074-5521(00)00063-6

Cited by 417 publications

(286 citation statements)

References 65 publications

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“…5) from crystals of apo protein that were soaked in solutions containing the compound (Table I). Hymenialdisine is a natural product found in marine sponges and has been shown to inhibit many protein kinases in an ATP-competitive manner (28). The compound occupies the ATP-binding pocket of ACK1K and binds in a manner similar to that described in a complex with CDK2 (28).…”

Section: Resultsmentioning

confidence: 99%

“…Hymenialdisine is a natural product found in marine sponges and has been shown to inhibit many protein kinases in an ATP-competitive manner (28). The compound occupies the ATP-binding pocket of ACK1K and binds in a manner similar to that described in a complex with CDK2 (28). In contrast to the nucleotide analog, the presence of the inhibitor causes a significant ordering of the nucleotidebinding loop.…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the Cdc42-associated Tyrosine Kinase ACK1

Lougheed

Chen

Mak

et al. 2004

Journal of Biological Chemistry

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ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5 -(␤,␥-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft.ACK1 (activated Cdc42-associated kinase-1) is a member of a small family of non-receptor tyrosine kinases that bind Cdc42 in its GTP-bound form. Members of the ACK family have been identified in many species, including human (TNK1) (1), cow (ACK2) (2), Drosophila (DAck, DPR2) (3, 4), and Caenorhabditis elegans (ARK1) (5). ACK1 is a multidomain protein, and all family members contain an SH3 1 domain and a C-terminal proline-rich region. ACK family members are largely expressed in brain and skeletal tissue (2), and multiple lines of evidence suggest that they are involved in the regulation of cell adhesion and growth (6), receptor degradation (7), and axonal guidance (3). ACK1 has been implicated as a mediator of epidermal growth factor signaling to Rho family GTP-binding proteins through phosphorylation and activation of guanosine exchange factors such as Dbl, suggesting a role in regulation of the cytoskeleton (8, 9). ACK1 has also been reported to bind to adaptor proteins, suggesting that it is involved in several different signaling pathways. The SH3 domain of ACK1 binds to the proline-rich region of HSH2, an adaptor protein in hematopoietic cells, leading to its phosphorylation (10), whereas the C-terminal proline-rich domain of ACK1 interacts with the adaptor proteins Nck (11) and Grb2 (12), which are involved in cytoskeletal rearrangement (13) and Ras activation (14), respectively. In addition, both DAck and ACK2 interact with the sorting nexin SH3PX1 through their C-terminal domains, leading to its phosphorylation (3, 7), and this ACK2 interaction with SH3PX1 together with clathrin promotes degradation of EGFR (7).The domain architecture of the ACK family is unique compared with other non-receptor tyrosine kinases, and ACK family members are the only tyrosine kinases known to interact with Cdc42 (15). Members of the ACK family are specific for Cdc42 and do not bind the closely related Rac and Rho GTPases (2, 15). The 114-kDa human ACK1 p...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the Cdc42-associated Tyrosine Kinase ACK1

Lougheed

Chen

Mak

et al. 2004

Journal of Biological Chemistry

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“…100 Pharmacological inhibitors of MARK/MARKK include staurosporine (unselectively) and hymenialdisine, which also inhibits GSK3␤. 90,101 Given the important and early role of MARK phosphorylation in the pathogenesis of tauopathies, the application of MARK inhibitors would be a worthwhile approach.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

“…110,111 Cdk5 inhibition can be achieved by active site-directed inhibitors, by 2,6,9-trisubstituted purines and aloisines, which are small-molecule inhibitors that interfere with the cdk5/p25 complex formation (Cdk5 inhibitory peptide [CIP]), and by calpain inhibitors, which prevent p25 generation. 101,112,113 The use of active site inhibitors is hampered by their lack of selectivity toward cdk5. Indirubins, which belong to the chemical class indolinones, also inhibit GSK-3.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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“…La chaîne robotique de KISSf permet le criblage de 2 500 composés par jour ( Figure 1 [15,32]. La sélectivité pharmacologique de l'hymenialdisine, ainsi que celle d'autres inhibiteurs caractérisés à Roscoff (dont la roscovitine [8] et l'aloisine [16]), a été étudiée par chromatographie d'affinité (fonctionnalisation des structures représentée sur la Figure 2).…”

Section: Les Protéine Kinases Des Cibles Thérapeutiques Impliquées Dunclassified

Le criblage à Roscoff

2015

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Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent

Abstract: The natural product hymenialdisine is a new kinase inhibitor with promising potential applications for treating neurodegenerative disorders.

Cited by 417 publications

References 65 publications

Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the Cdc42-associated Tyrosine Kinase ACK1

Crystal Structures of the Phosphorylated and Unphosphorylated Kinase Domains of the Cdc42-associated Tyrosine Kinase ACK1

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Le criblage à Roscoff

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