Identification of new kinase clusters required for neurite outgrowth and retraction by a loss-of-function RNA interference screen

Loh, Samantha H. Y.; Francescut, Lorenza; Lingor, Paul; Bähr, Mathias; Nicotera, Pierluigi

doi:10.1038/sj.cdd.4402258

Cited by 86 publications

(109 citation statements)

References 42 publications

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“…In mammalian cells, MAP4K4 was identified in a high-throughput screen for regulators of neurite outgrowth. 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].…”

Section: Axon Navigation and Neurite Outgrowthsupporting

confidence: 65%

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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Section: Axon Navigation and Neurite Outgrowthsupporting

confidence: 65%

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

Tripolitsioti¹,

Grotzer²,

Baumgärtner³

2017

J Carcinog Mutagen

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“…ANL calculations are described in detail in Ref. 10. Because both of the total neurite length and neuron cell number are statistical results averaged over entire image, ANL is a robust measure of neurite outgrowth which is highly accurate and reproducible even in high density cultures.…”

Section: Methodsmentioning

confidence: 99%

Identification of Small Molecule Inhibitors of Neurite Loss Induced by Aβ peptide using High Content Screening

Ofengeim

Shi

Miao

et al. 2012

Journal of Biological Chemistry

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Background: Amyloid-␤-induced degeneration of neurites is a key event in Alzheimer disease. Results: We describe NeuriteIQ high content screening platform for analysis of neurite degeneration. Conclusion: We identified multiple cyclooxygenase inhibitors and agonists of PPAR␥ as suppressors of A␤-induced neurite loss. Significance: Our study demonstrates the feasibility of using NeuriteQ to discover inhibitors of neurite loss and provide a new insight into neurite degeneration.

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“…Furthermore, in some cells ULK1 has functions in addition to autophagy, such as in axonal transport and outgrowth, and its activity state may thus reflect its role in these processes. [390][391][392][393][394][395] Accordingly, other methods as described throughout these guidelines should also be used to follow autophagy directly.…”

mentioning

confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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Identification of new kinase clusters required for neurite outgrowth and retraction by a loss-of-function RNA interference screen

Cited by 86 publications

References 42 publications

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

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

Identification of Small Molecule Inhibitors of Neurite Loss Induced by Aβ peptide using High Content Screening

Guidelines for the use and interpretation of assays for monitoring autophagy

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