DYRK1B regulates Hedgehog-induced microtubule acetylation

Singh, Rajeev; Holz, Philipp Simon; Roth, Katrin; Hupfer, Anna; Meißner, Wolfgang; Müller, Rolf; Buchholz, Malte; Gress, Thomas M.; Elsässer, Hans–Peter; Jacob, Ralf; Lauth, Matthias

doi:10.1007/s00018-018-2942-5

Cited by 10 publications

(7 citation statements)

References 84 publications

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“…Pharmacological inhibition of DYRK1B could downregulated Akt phosphorylation at Ser473 and Thr308 in human pancreatic and ovarian cells 18 . Increased DYRK1B kinase resulted in the inhibition of GSK-3β through phosphorylation of Ser9 in mouse embryonic fibroblasts 29 . These evidences strongly supported our findings in HCC.…”

Section: Discussionmentioning

confidence: 99%

TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression

Wei

Song

et al. 2021

Cell Death Dis

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Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.

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Section: Discussionmentioning

confidence: 99%

TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression

Wei

Song

et al. 2021

Cell Death Dis

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“…It negatively interferes with SMO-elicited canonical HH signaling, while at the same time it promotes AKT-mediated GLI1 stability [82]. More recently, it has been shown that DYRK1B regulates HH-induced microtubule acetylation [83].…”

Section: The Major Phosphorylation Events In Hedgehog Pathway: Thementioning

confidence: 99%

Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy

Montagnani

Stecca

2019

Cancers

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Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy.

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“…Highly prominent intercellular Hedgehog signaling (Hh) increases the MT-associated DYRK1B kinase levels, which subsequently leads to the decrease of HDAC6 level and thereby modulates MT acetylation. DYRK1B-mediated Hh signaling activation also increases the intracellular transport of mitochondria, implying the beneficial role of acetylated MTs in organelle transport [ 171 ]. All these findings signify the critical role of tubulin acetylation in the pathological framework of diseases [ 26 , 149 , 167 , 172 ].…”

Section: Ptms Of Tubulin – Limelight On Acetylationmentioning

confidence: 99%

“…SAHA has proceeded to a phase 1 clinical trial for AD (NCT03056495), and a recruiting study in PD patients has been designed at a very small and minimal scale (NCT03977740). Increase of acetylated tubulin levels by yet another small-molecule HDAC6 inhibitor, ACY-1215, leads to a parallel significant increase of speed and track length of mitochondrial transport [ 171 ]. The novel compound N -[(1R,2R)-2-{3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}cyclohexyl]-2,2,3,3,3-pentafluoropropanamide, T-518 in short, is a potent and highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics that induces a significant increase in tubulin acetylation in the hippocampus of P301S tau transgenic mice.…”

Section: Therapeutic Strategies For Enhancing Tubulin Acetylationmentioning

confidence: 99%

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Naren

Samim

Tryphena

et al. 2023

Transl Neurodegener

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The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it. Graphical abstract

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DYRK1B regulates Hedgehog-induced microtubule acetylation

Cited by 10 publications

References 84 publications

TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression

TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression

Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy

Microtubule acetylation dyshomeostasis in Parkinson’s disease

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