IGFBP‐2 stimulates calcium/calmodulin‐dependent protein kinase kinase 2 activation leading to AMP‐activated protein kinase induction which is required for osteoblast differentiation

2019 ◽  
Vol 234 (12) ◽  
pp. 23232-23242 ◽  
Author(s):  
Gang Xi ◽  
Susan D'Costa ◽  
Christine Wai ◽  
Shalier K. Xia ◽  
Zach C. Cox ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Osteoblast Differentiation ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Amp Activated Protein Kinase ◽  
Protein Kinase Kinase

scholarly journals Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gerson S. Profeta ◽  
Caio V. dos Reis ◽  
André da S. Santiago ◽  
Paulo H. C. Godoi ◽  
Angela M. Fala ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Titration Calorimetry ◽  
Dependent Protein Kinase ◽  
Regulatory Pathways ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Amp Activated Protein Kinase ◽  
Protein Kinase Kinase

Abstract Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such as AMPK (AMP-activated protein kinase) and CAMK types I and IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this protein kinase. Moreover, CAMKK2 and its closest human homolog, CAMKK1, are thought to have overlapping biological roles. Here we present six new co-structures of potent ligands bound to CAMKK2 identified from a library of commercially-available kinase inhibitors. Enzyme assays confirmed that most of these compounds are equipotent inhibitors of both human CAMKKs and isothermal titration calorimetry (ITC) revealed that binding to some of these molecules to CAMKK2 is enthalpy driven. We expect our results to advance current efforts to discover small molecule kinase inhibitors selective to each human CAMKK.

scholarly journals 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (5) ◽  
pp. 1221 ◽  
Author(s):  
Christopher Asquith ◽  
Paulo Godoi ◽  
Rafael Couñago ◽  
Tuomo Laitinen ◽  
John Scott ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Narrow Spectrum ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Protein Kinase Kinase

scholarly journals Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β Is Detrimental in Hypoxia–Ischemia Neonatal Brain Injury

2019 ◽  
Vol 20 (9) ◽  
pp. 2063
Author(s):  
Jia-Wei Min ◽  
Fan Bu ◽  
Li Qi ◽  
Yashasvee Munshi ◽  
Gab Seok Kim ◽  
...  
Keyword(s):  
Brain Injury ◽  
Protein Kinase ◽  
Intracellular Calcium ◽  
Infarct Volume ◽  
Dependent Protein Kinase ◽  
Neonatal Hypoxia ◽  
Calcium Calmodulin Dependent ◽  
Hypoxia Ischemia ◽  
Dependent Protein ◽  
Protein Kinase Kinase

Neonatal hypoxia–ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways. Calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) is a major kinase activated by elevated levels of intracellular calcium. Here we evaluated the functional role of CaMKK β in neonatal mice after HI in both acute and chronic survival experiments. Postnatal day ten wild-type (WT) and CaMKK β knockout (KO) mouse male pups were subjected to unilateral carotid artery ligation, followed by 40 min of hypoxia (10% O2 in N2). STO-609, a CaMKK inhibitor, was administered intraperitoneally to WT mice at 5 minutes after HI. TTC (2,3,5-triphenyltetrazolium chloride monohydrate) staining was used to assess infarct volume 24 h after HI. CaMKK β KO mice had larger infarct volume than WT mice and STO-609 increased the infarct volume in WT mice after HI. In chronic survival experiments, WT mice treated with STO-609 showed increased tissue loss in the ipsilateral hemisphere three weeks after HI. Furthermore, when compared with vehicle-treated mice, they showed poorer functional recovery during the three week survival period, as measured by the wire hang test and corner test. Loss of blood–brain barrier proteins, a reduction in survival protein (Bcl-2), and an increase in pro-apoptotic protein Bax were also seen after HI with CaMKK β inhibition. In conclusion, inhibition of CaMKK β exacerbated neonatal hypoxia–ischemia injury in mice. Our data suggests that enhancing CaMKK signaling could be a potential target for the treatment of hypoxic–ischemic brain injury.

Evidence for the involvement of CaMKII and AMPK in Ca2+-dependent signaling pathways regulating FA uptake and oxidation in contracting rodent muscle

2008 ◽  
Vol 104 (5) ◽  
pp. 1366-1373 ◽  
Author(s):  
Marcella A. Raney ◽  
Lorraine P. Turcotte
Keyword(s):  
Electrical Stimulation ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Calcium Calmodulin Dependent ◽  
Extracellular Signal ◽  
Regulation Of Contraction ◽  
Dependent Protein ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Calcium-calmodulin/dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK1/2) have each been implicated in the regulation of substrate metabolism during exercise. The purpose of this study was to determine whether CaMKII is involved in the regulation of FA uptake and oxidation and, if it is involved, whether it does so independently of AMPK and ERK1/2. Rat hindquarters were perfused at rest with ( n = 16) or without ( n = 10) 3 mM caffeine, or during electrical stimulation ( n = 14). For each condition, rats were subdivided and treated with 10 μM of either KN92 or KN93, inactive and active CaMKII inhibitors, respectively. Both caffeine treatment and electrical stimulation significantly increased FA uptake and oxidation. KN93 abolished caffeine-induced FA uptake, decreased contraction-induced FA uptake by 33%, and abolished both caffeine- and contraction-induced FA oxidation ( P < 0.05). Caffeine had no effect on ERK1/2 phosphorylation ( P > 0.05) and increased α2-AMPK activity by 68% ( P < 0.05). Electrical stimulation increased ERK1/2 phosphorylation and α2-AMPK activity by 51% and 3.4-fold, respectively ( P < 0.05). KN93 had no effect on caffeine-induced α2-AMPK activity, ERK1/2 phosphorylation, or contraction-induced ERK1/2 phosphorylation ( P > 0.05). Alternatively, it decreased contraction-induced α2-AMPK activity by 51% ( P < 0.05), suggesting that CaMKII lies upstream of AMPK. These results demonstrate that regulation of contraction-induced FA uptake and oxidation occurs in part via Ca2+-independent activation of ERK1/2 as well as Ca2+-dependent activation of CaMKII and AMPK.

scholarly journals Differential AMP-activated Protein Kinase (AMPK) Recognition Mechanism of Ca2+/Calmodulin-dependent Protein Kinase Kinase Isoforms

2016 ◽  
Vol 291 (26) ◽  
pp. 13802-13808 ◽  
Author(s):  
Yuya Fujiwara ◽  
Yoshinori Kawaguchi ◽  
Tomohito Fujimoto ◽  
Naoki Kanayama ◽  
Masaki Magari ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Recognition Mechanism ◽  
Dependent Protein ◽  
Amp Activated Protein Kinase ◽  
Protein Kinase Kinase
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