New Candidate Targets of AMP-Activated Protein Kinase in Murine Brain Revealed by a Novel Multidimensional Substrate-Screen for Protein Kinases

2007 ◽  
Vol 6 (8) ◽  
pp. 3266-3277 ◽  
Author(s):  
Roland D. Tuerk ◽  
Ramon F. Thali ◽  
Yolanda Auchli ◽  
Helene Rechsteiner ◽  
René A. Brunisholz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Murine Brain ◽  
Amp Activated Protein Kinase

scholarly journals The ubiquitin-associated domain of AMPK-related protein kinases allows LKB1-induced phosphorylation and activation

2006 ◽  
Vol 394 (3) ◽  
Author(s):  
Mark H. Rider
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Related Protein ◽  
Biochemical Journal ◽  
Kinase Catalytic Domain ◽  
Uba Domain ◽  
Amp Activated Protein Kinase

The AMPK (AMP-activated protein kinase)-related protein kinase subfamily of the human kinome comprises 12 members closely related to the catalytic α1/α2 subunits of AMPK. The precise role of the AMPK-related kinases and their in vivo substrates is rather unclear at present, but some are involved in regulating cell polarity, whereas others appear to control cellular differentiation. Of the 12 human AMPK-related protein kinase family members, 11 can be activated following phosphorylation of their T-loop threonine residue by the LKB1 complex. Nine of these AMPK-related kinases activated by LKB1 contain an UBA (ubiquitin-associated) domain immediately C-terminal to the kinase catalytic domain. In this issue of the Biochemical Journal, Jaleel et al. show that the presence of an UBA domain in AMP-related kinases allows LKB1-induced phosphorylation and activation. The findings have implications for understanding the molecular mechanisms of activation of this fascinating family of protein kinases. Also, mutations in the UBA domains of the AMP-related kinase genes might be present in families with Peutz–Jehgers syndrome and in other cancer patients.

Snf1-related protein kinases (SnRKs) act within an intricate network that links metabolic and stress signalling in plants

2009 ◽  
Vol 419 (2) ◽  
pp. 247-259 ◽  
Author(s):  
Nigel G. Halford ◽  
Sandra J. Hey
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Signalling Pathways ◽  
Related Protein ◽  
Major Mechanism ◽  
Intracellular Signals ◽  
Kinase Cascade ◽  
Eukaryotic Organisms ◽  
Amp Activated Protein Kinase ◽  
Stress Signalling

The phosphorylation and dephosphorylation of proteins, catalysed by protein kinases and phosphatases, is the major mechanism for the transduction of intracellular signals in eukaryotic organisms. Signalling pathways often comprise multiple phosphorylation/dephosphorylation steps and a long-standing hypothesis to explain this phenomenon is that of the protein kinase cascade, in which a signal is amplified as it is passed from one step in a pathway to the next. This review represents a re-evaluation of this hypothesis, using the signalling network in which the SnRKs [Snf1 (sucrose non-fermenting-1)-related protein kinases] function as an example, but drawing also on the related signalling systems involving Snf1 itself in fungi and AMPK (AMP-activated protein kinase) in animals. In plants, the SnRK family comprises not only SnRK1, but also two other subfamilies, SnRK2 and SnRK3, with a total of 38 members in the model plant Arabidopsis. This may have occurred to enable linking of metabolic and stress signalling. It is concluded that signalling pathways comprise multiple levels not to allow for signal amplification, but to enable linking between pathways to form networks in which key protein kinases, phosphatases and target transcription factors represent hubs on/from which multiple pathways converge and emerge.

scholarly journals The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation

2006 ◽  
Vol 394 (3) ◽  
pp. 545-555 ◽  
Author(s):  
Mahaboobi Jaleel ◽  
Fabrizio Villa ◽  
Maria Deak ◽  
Rachel Toth ◽  
Alan R. Prescott ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Catalytic Domain ◽  
Limited Proteolysis ◽  
Cancer Syndrome ◽  
Tumour Suppressor Protein ◽  
Kinase Catalytic Domain ◽  
Uba Domain ◽  
Significant Conformational Change ◽  
Amp Activated Protein Kinase

Recent work indicates that the LKB1 tumour suppressor protein kinase, which is mutated in Peutz–Jeghers cancer syndrome, phosphorylates and activates a group of protein kinases that are related to AMPK (AMP-activated protein kinase). Ten of the 14 AMPK-related protein kinases activated by LKB1, including SIK (salt-induced kinase), MARK (microtubule-affinity-regulating kinase) and BRSK (brain-specific kinase) isoforms, possess a ubiquitin-associated (UBA) domain immediately C-terminal to the kinase catalytic domain. These are the only protein kinases in the human genome known to possess a UBA domain, but their roles in regulating AMPK-related kinases are unknown. We have investigated the roles that the UBA domain may play in regulating these enzymes. Limited proteolysis of MARK2 revealed that the kinase and UBA domains were contained within a fragment that was resistant to trypsin proteolysis. SAXS (small-angle X-ray scattering) analysis of inactive and active LKB1-phosphorylated MARK2 revealed that activation of MARK2 is accompanied by a significant conformational change that alters the orientation of the UBA domain with respect to the catalytic domain. Our results indicate that none of the UBA domains found in AMPK-related kinases interact with polyubiquitin or other ubiquitin-like molecules. Instead, the UBA domains appear to play an essential conformational role and are required for the LKB1-mediated phosphorylation and activation of AMPK-related kinases. This is based on the findings that mutation or removal of the UBA domains of several AMPK-related kinases, including isoforms of MARK, SIK and BRSK, markedly impaired the catalytic activity and LKB1-mediated phosphorylation of these enzymes. We also provide evidence that the UBA domains do not function as LKB1–STRAD (STE20-related adaptor)–MO25 (mouse protein 25) docking/interacting sites and that mutations in the UBA domain of SIK suppressed the ability of SIK to localize within punctate regions of the nucleus. Taken together, these findings suggest that the UBA domains of AMPK-related kinases play an important role in regulating the conformation, activation and localization of these enzymes.

AMP-activated protein kinase regulates PDGF-BB-stimulated interleukin-6 synthesis in osteoblasts: Involvement of mitogen-activated protein kinases

Life Sciences ◽  
2012 ◽  
Vol 90 (1-2) ◽  
pp. 71-76 ◽  
Author(s):  
Kenji Kato ◽  
Takanobu Otsuka ◽  
Akira Kondo ◽  
Rie Matsushima-Nishiwaki ◽  
Hideo Natsume ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Interleukin 6 ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
Amp Activated Protein Kinase
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