scholarly journals TTBK2: A Tau Protein Kinase beyond Tau Phosphorylation

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jung-Chi Liao ◽  
T. Tony Yang ◽  
Rueyhung Roc Weng ◽  
Ching-Te Kuo ◽  
Chih-Wei Chang
Keyword(s):  
Binding Sites ◽  
Kinase Domain ◽  
Tau Phosphorylation ◽  
Spinocerebellar Ataxia Type ◽  
Mitotic Spindles ◽  
Sequence Structure ◽  
Casein Kinase 1 ◽  
Gaba Transport ◽  
Cellular Processes ◽  
Amino Acid Segment

Tau tubulin kinase 2 (TTBK2) is a kinase known to phosphorylate tau and tubulin. It has recently drawn much attention due to its involvement in multiple important cellular processes. Here, we review the current understanding of TTBK2, including its sequence, structure, binding sites, phosphorylation substrates, and cellular processes involved. TTBK2 possesses a casein kinase 1 (CK1) kinase domain followed by a ~900 amino acid segment, potentially responsible for its localization and substrate recruitment. It is known to bind to CEP164, a centriolar protein, and EB1, a microtubule plus-end tracking protein. In addition to autophosphorylation, known phosphorylation substrates of TTBK2 include tau, tubulin, CEP164, CEP97, and TDP-43, a neurodegeneration-associated protein. Mutations of TTBK2 are associated with spinocerebellar ataxia type 11. In addition, TTBK2 is essential for regulating the growth of axonemal microtubules in ciliogenesis. It also plays roles in resistance of cancer target therapies and in regulating glucose and GABA transport. Reported sites of TTBK2 localization include the centriole/basal body, the midbody, and possibly the mitotic spindles. Together, TTBK2 is a multifunctional kinase involved in important cellular processes and demands augmented efforts in investigating its functions.

Merlin cooperates with neurofibromin and Spred1 to suppress the Ras–Erk pathway

2020 ◽  
Author(s):  
Yan Cui ◽  
Lin Ma ◽  
Stephan Schacke ◽  
Jiani C Yin ◽  
Yi-Ping Hsueh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Binding Sites ◽  
Neurofibromatosis Type ◽  
Kinase Domain ◽  
Erk Pathway ◽  
Suppressor Activity ◽  
The Third ◽  
Tumor Suppressor Activity ◽  
Multiple Signaling

Abstract The Ras–Erk pathway is frequently over-activated in human tumors. Neurofibromatosis type 1 and 2 (NF1, NF2) are characterized by multiple tumors of Schwann cell origin. The NF1 tumor suppressor neurofibromin is a principal Ras-GAP accelerating Ras inactivation, whereas the NF2 tumor suppressor merlin is a scaffold protein coordinating multiple signaling pathways. We have previously reported that merlin interacts with Ras and p120RasGAP. Here, we show that merlin can also interact with the neurofibromin/Spred1 complex via merlin-binding sites present on both proteins. Further, merlin can directly bind to the Ras-binding domain and the kinase domain of Raf1. As the third component of the neurofibromin/Spred1 complex, merlin cannot increase the Ras-GAP activity; rather, it blocks Ras binding to Raf1 by functioning as a ‘selective Ras barrier’. Merlin-deficient Schwann cells require the Ras–Erk pathway activity for proliferation. Accordingly, suppression of the Ras–Erk pathway likely contributes to merlin’s tumor suppressor activity. Taken together, our results, and studies by others, support targeting or co-targeting of this pathway as a therapy for NF2 inactivation-related tumors.

scholarly journals Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shirley Tremel ◽  
Yohei Ohashi ◽  
Dustin R. Morado ◽  
Jessie Bertram ◽  
Olga Perisic ◽  
...  
Keyword(s):  
Complex I ◽  
Kinase Domain ◽  
Beclin 1 ◽  
Structural Basis ◽  
Rab Gtpases ◽  
Lipid Kinase ◽  
Complex Ii ◽  
Cellular Processes ◽  
Specific Complex ◽  
Electron Cryotomography

AbstractThe lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations.

scholarly journals Mapping the glycosyltransferase fold landscape using interpretable deep learning

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rahil Taujale ◽  
Zhongliang Zhou ◽  
Wayland Yeung ◽  
Kelley W. Moremen ◽  
Sheng Li ◽  
...  
Keyword(s):  
Deep Learning ◽  
Secondary Structure ◽  
Structural Features ◽  
Functional Diversification ◽  
Sequence Structure ◽  
Cellular Processes ◽  
And Function ◽  
Deep Learning Model ◽  
Fold Prediction ◽  
Primary Sequence Alignment

AbstractGlycosyltransferases (GTs) play fundamental roles in nearly all cellular processes through the biosynthesis of complex carbohydrates and glycosylation of diverse protein and small molecule substrates. The extensive structural and functional diversification of GTs presents a major challenge in mapping the relationships connecting sequence, structure, fold and function using traditional bioinformatics approaches. Here, we present a convolutional neural network with attention (CNN-attention) based deep learning model that leverages simple secondary structure representations generated from primary sequences to provide GT fold prediction with high accuracy. The model learns distinguishing secondary structure features free of primary sequence alignment constraints and is highly interpretable. It delineates sequence and structural features characteristic of individual fold types, while classifying them into distinct clusters that group evolutionarily divergent families based on shared secondary structural features. We further extend our model to classify GT families of unknown folds and variants of known folds. By identifying families that are likely to adopt novel folds such as GT91, GT96 and GT97, our studies expand the GT fold landscape and prioritize targets for future structural studies.

scholarly journals SSMART: Sequence-structure motif identification for RNA-binding proteins

2018 ◽  
Author(s):  
Alina Munteanu ◽  
Neelanjan Mukherjee ◽  
Uwe Ohler
Keyword(s):  
Binding Sites ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Sequence Motif ◽  
Primary Sequence ◽  
Sequence Structure ◽  
Rna Targets

AbstractMotivationRNA-binding proteins (RBPs) regulate every aspect of RNA metabolism and function. There are hundreds of RBPs encoded in the eukaryotic genomes, and each recognize its RNA targets through a specific mixture of RNA sequence and structure properties. For most RBPs, however, only a primary sequence motif has been determined, while the structure of the binding sites is uncharacterized.ResultsWe developed SSMART, an RNA motif finder that simultaneously models the primary sequence and the structural properties of the RNA targets sites. The sequence-structure motifs are represented as consensus strings over a degenerate alphabet, extending the IUPAC codes for nucleotides to account for secondary structure preferences. Evaluation on synthetic data showed that SSMART is able to recover both sequence and structure motifs implanted into 3‘UTR-like sequences, for various degrees of structured/unstructured binding sites. In addition, we successfully used SSMART on high-throughput in vivo and in vitro data, showing that we not only recover the known sequence motif, but also gain insight into the structural preferences of the RBP.AvailabilitySSMART is freely available at https://ohlerlab.mdc-berlin.de/software/SSMART_137/[email protected]

scholarly journals Tyr198 is the Essential Autophosphorylation Site for STK16 Localization and Kinase Activity

2019 ◽  
Vol 20 (19) ◽  
pp. 4852 ◽  
Author(s):  
Junjun Wang ◽  
Juanjuan Liu ◽  
Xinmiao Ji ◽  
Xin Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Kinase Domain ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Threonine Kinase ◽  
Cellular Processes ◽  
Activation Segment ◽  
And Function

STK16, reported as a Golgi localized serine/threonine kinase, has been shown to participate in multiple cellular processes, including the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. However, the mechanisms of the regulation of its kinase activity remain underexplored. It was known that STK16 is autophosphorylated at Thr185, Ser197, and Tyr198 of the activation segment in its kinase domain. We found that STK16 localizes to the cell membrane and the Golgi throughout the cell cycle, but mutations in the auto-phosphorylation sites not only alter its subcellular localization but also affect its kinase activity. In particular, the Tyr198 mutation alone significantly reduced the kinase activity of STK16, abolished its Golgi and membrane localization, and affected the cell cycle progression. This study demonstrates that a single site autophosphorylation of STK16 could affect its localization and function, which provides insights into the molecular regulatory mechanism of STK16’s kinase activity.

Integrin regulation of membrane domain trafficking and Rac targeting

2005 ◽  
Vol 33 (4) ◽  
pp. 609-613 ◽  
Author(s):  
A. Grande-García ◽  
A. Echarri ◽  
M.A. Del Pozo
Keyword(s):  
Cell Growth ◽  
Binding Sites ◽  
Cell Cycle Progression ◽  
Membrane Microdomains ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
And Migration ◽  
Integrin Regulation

Integrins are crucial regulators of essential cellular processes such as gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins critically regulate Rho family GTPases, that are also involved in cell-cycle progression and oncogenesis. In addition to their effect on GTP loading, integrins independently control the translocation of GTP-bound Rac to the plasma membrane. This step is essential for Rac binding to effectors. Integrins increase membrane affinity for Rac, leading to RhoGDI dissociation and effector coupling locally, in the vicinity of activated/bound integrins. Integrin-regulated Rac binding sites are within CEMMs (cholesterol-enriched membrane microdomains). Integrins control Rac signalling by preventing the internalization of its binding sites in CEMMs. Integrin regulation of signalling pathways initiated in CEMMs may be important for the spatial control of cell migration and anchorage dependence of cell growth.

scholarly journals Ribosomal S6 Kinase (RSK) Regulates Phosphorylation of Filamin A on an Important Regulatory Site

2004 ◽  
Vol 24 (7) ◽  
pp. 3025-3035 ◽  
Author(s):  
Michele S. Woo ◽  
Yasutaka Ohta ◽  
Isaac Rabinovitz ◽  
Thomas P. Stossel ◽  
John Blenis
Keyword(s):  
Map Kinase ◽  
Kinase Domain ◽  
Filamin A ◽  
S6 Kinase ◽  
Membrane Ruffling ◽  
Cellular Processes ◽  
Mitogen Activated Protein ◽  
Epidermal Growth ◽  
Ribosomal S6 Kinase

ABSTRACT The Ras-mitogen-activated protein (Ras-MAP) kinase pathway regulates various cellular processes, including gene expression, cell proliferation, and survival. Ribosomal S6 kinase (RSK), a key player in this pathway, modulates the activities of several cytoplasmic and nuclear proteins via phosphorylation. Here we report the characterization of the cytoskeletal protein filamin A (FLNa) as a membrane-associated RSK target. We show that the N-terminal kinase domain of RSK phosphorylates FLNa on Ser2152 in response to mitogens. Inhibition of MAP kinase signaling with UO126 or mutation of Ser2152 to Ala on FLNa prevents epidermal growth factor (EGF)-stimulated phosphorylation of FLNa in vivo. Furthermore, phosphorylation of FLNa on Ser2152 is significantly enhanced by the expression of wild-type RSK and antagonized by kinase-inactive RSK or specific reduction of endogenous RSK. Strikingly, EGF-induced, FLNa-dependent migration of human melanoma cells is significantly reduced by UO126 treatment. Together, these data provide substantial evidence that RSK phosphorylates FLNa on Ser2152 in vivo. Given that phosphorylation of FLNa on Ser2152 is required for Pak1-mediated membrane ruffling, our results suggest a novel role for RSK in the regulation of the actin cytoskeleton.

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