Neuritogenic Militarinone‐Inspired 4‐Hydroxypyridones Target the Stress Pathway Kinase MAP4K4

Schröder, Peter; Förster, Tim; Kleine, Stefan; Becker, C.J.; Richters, André; Ziegler, Slava; Rauh, Daniel; Kumar, Kamal; Waldmann, Herbert

doi:10.1002/ange.201501515

Cited by 20 publications

(13 citation statements)

References 48 publications

(31 reference statements)

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“…22 Additionally, MAP4K4 inhibitors with more poorly characterized specificity have been shown to affect neurite outgrowth. 23 However, it is not clear if neurite outgrowth is regulated by MAP4K4-dependent phosphorylation or by protein−protein interactions. Therefore, we treated SH-SY5Y cells with vehicle, compound 1, or staurosporine, a positive control for neurite outgrowth, and measured neurite length per cell ( Figure 4B,C and Supporting Information Figure S7; magnified images, Figure S8).…”

Section: * S Supporting Informationmentioning

confidence: 99%

MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1

Schwaid¹,

Su²,

Loos³

et al. 2015

ACS Chem. Biol.

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Mitogen-activated protein kinase 4 (MAP4K4) regulates the MEK kinase cascade and is implicated in cytoskeletal rearrangement and migration; however, identifying MAP4K4 substrates has remained a challenge. To ascertain MAP4K4-dependent phosphorylation events, we combined phosphoproteomic studies of MAP4K4 inhibition with in vitro assessment of its kinase specificity. We identified 235 phosphosites affected by MAP4K4 inhibition in cells and found that pTP and pSP motifs were predominant among them. In contrast, in vitro assessment of kinase specificity showed that MAP4K4 favors a pTL motif. We showed that MAP4K4 directly phosphorylates and coimmunoprecipitates with FERM, RhoGEF, and pleckstrin domain-containing protein 1 (FARP1). MAP4K4 inhibition in SH-SY5Y cells increases neurite outgrowth, a process known to involve FARP1. As FARP1 and MAP4K4 both contribute to cytoskeletal rearrangement, the results suggest that MAP4K4 exerts some of its effects on the cytoskeleton via phosphorylation of FARP1.

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Section: * S Supporting Informationmentioning

confidence: 99%

MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1

Schwaid¹,

Su²,

Loos³

et al. 2015

ACS Chem. Biol.

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“…In contrast to its neuro-promoting functions during development, MAP4K4 depletion in cerebellar granule neurons significantly increased the length of regenerating neurites, suggesting that MAP4K4 in mammals restricts neuronal outgrowth [45]. This finding was confirmed by an unrelated study using a militarinone-inspired 4-hydroxy-2-pyridone inhibitor targeting MAP4K4, which resulted in neuritogenesis [46]. MAP4K4 inhibition is also a reported target of kenpaullone, an inhibitor of Amyotrophic Lateral Sclerosis (ALS) [47].…”

Section: Axon Navigation and Neurite Outgrowthmentioning

confidence: 89%

“…MAP4K4 is highly expressed in the brain tissue and its implications in neurodegenerative disorders have been addressed in the context of a search for natural products with neurotrophic and/or neuroprotective activities [46]. One such bioactive compound -militarinone-A -was identified as metabolite of a Cordycept fungus.…”

Section: Therapeutics Targeting Map4k4 Functionsmentioning

confidence: 99%

“…To evaluate the neurotrophic activity of those Militarinone-A analogs, they were subjected to phenotypic screening in the human neuroblastoma cell line SH-SY5Y. Compound 11e enhanced neurite outgrowth and inhibited MAP4K4 kinase activity in vitro, making it a suitable starting compound for future studies related to neurological disorders and -possibly -also MAP4K4-dependent brain tumors [46].…”

Section: Therapeutics Targeting Map4k4 Functionsmentioning

confidence: 99%

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The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions

Tripolitsioti¹,

Grotzer²,

Baumgärtner³

2017

J Carcinog Mutagen

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The search for novel targeted therapies for major human conditions such as diabetes, cardiovascular diseases and cancer is a slow and costly process. Progress is often hampered by poor drug efficaciousness in the patients, low selectivity/specificity of the compounds and cellular evasion mechanism that are rather common in anti-cancer therapies. This is particularly true also for compounds inhibiting kinases, which in theory are optimal targets thanks to their druggable enzymatic activity. Novel targeting strategies are needed to reduce side effects and treatment failure caused by non-specific drug function and target resistance, respectively. An ideal compound will repress the relevant kinase effector function, while leaving kinase functions that are not disease-relevant unaltered. To achieve function-specific inhibition, the molecular mechanism of the drug target that governs the pathological process, must be identified.The Ser/Thr kinase MAP4K4 is implicated in inflammatory and metabolic disorders and cancer progression. In this review, we describe the molecular effector functions of MAP4K4 that exert those activities and how they have been identified and characterized both in invertebrate organisms and mammals. We discuss how the modulation of the cellular cytoskeleton by MAP4K4 may be connected to pathological conditions such as aberrant angiogenesis and cancer metastasis, and we describe the molecular mechanisms that are so far known to be mechanistically involved in these processes.

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“…All these alkaloids have also been prepared synthetically (Baldwin et Many natural products have shown to possess neuritogenic activity in cell and animal models (Faulkner, 2000), and alkaloids with 4-hydroxy-2-pyridone core structure belong to this group of substances. These are selective ATP-competitive inhibitors of mitogen-activated protein kinase (MAP4K4) but not of the other stress pathway related kinases (Schröder et al, 2015). Numerous studies in recent years show that MAP4K4 may be a new target for the treatment of neurodegenerative diseases (Yang et al, 2011).…”

Section: Alkaloidsmentioning

confidence: 99%

BIOACTIVE METABOLITES OF ENTOMOPATHOGENIC FUNGI Beauveria bassiana

Patočka¹

2016

Mil. Med. Sci. Lett.

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SummaryBeauveria bassiana is a fungus which causes disease in insects. Currently it is used as an insecticide to control pest populations. Fungi are known to produce a vast array of secondary metabolites that are important for biotechnological applications. Furthemore, B. bassiana is an interesting source of biologically active molecules. There are alkaloids with the structure of 2-pyridone, dibenzoquinone pigments and different cyclodepsipeptides. Cyclodepsipeptides from B. bassiana are interesting for their neuroprotective properties. Interest of psychopharmacology is focused on the group of beauveriolides. Plant B. bassiana becomes a candidate for the prevention and treatment of neurodegenerative diseases.

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Neuritogenic Militarinone‐Inspired 4‐Hydroxypyridones Target the Stress Pathway Kinase MAP4K4

Cited by 20 publications

References 48 publications

MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1

MAP4K4 Is a Threonine Kinase That Phosphorylates FARP1

The Ser/Thr Kinase MAP4K4 Controls Pro-Metastatic Cell Functions

BIOACTIVE METABOLITES OF ENTOMOPATHOGENIC FUNGI Beauveria bassiana

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