Ca2+/Calmodulin-dependent Protein Kinase Kinase β Is Regulated by Multisite Phosphorylation

Green, Michelle; Scott, John W.; Steel, Rohan; Oakhill, Jonathan S.; Kemp, Bruce E.; Means, Anthony R.

doi:10.1074/jbc.m111.251504

Cited by 61 publications

(82 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, phosphorylation of Ser-129, Ser-133, and Ser-137 also increases the stability of CaMKK2. CDK5 (cyclin-dependent kinase 5) and GSK3 (glycogen synthase kinase 3) have been identified as upstream kinases responsible for phosphorylating these sites and, in turn, for the regulation of the autonomous activity of CaMKK2 (27). Furthermore, it has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of Thr-482, a post-translational change that likely contributes to the increased autonomous activity of CaMKK2 ( Fig.…”

Section: Camkk2: Structure and Functionmentioning

confidence: 99%

“…By using truncation mutants of CaMKK2, a region of 23 amino acids (residues 129 -151) located N-terminal to the catalytic domain was identified as an important regulatory element of autonomous activity (26). Mass spectrometry revealed three phosphorylation sites, Ser-129, Ser-133, and Ser-137 (26,27), which are highly conserved in mouse, rat, and human isoforms of CaMKK2. CaMKK2 with mutations of these Ser residues exhibits increased autonomous activity but no change in Ca 2ϩ /CaMdependent activity (27).…”

Section: Camkk2: Structure and Functionmentioning

confidence: 99%

“…Mass spectrometry revealed three phosphorylation sites, Ser-129, Ser-133, and Ser-137 (26,27), which are highly conserved in mouse, rat, and human isoforms of CaMKK2. CaMKK2 with mutations of these Ser residues exhibits increased autonomous activity but no change in Ca 2ϩ /CaMdependent activity (27). Notably, phosphorylation of Ser-129, Ser-133, and Ser-137 also increases the stability of CaMKK2.…”

Section: Camkk2: Structure and Functionmentioning

confidence: 99%

“…CaMKK and CaMKI co-localize with ␤PIX (p21-activated kinase-interacting exchange factor) and GIT1 (G-protein-coupled receptor kinase-interacting protein 1) in dendritic spines as part of a multiprotein complex that regulates actin dynamics (43). Differential splicing and phosphorylation of critical Ser residues affect the ability of CaMKK2 to control dendrite/axon formation (17,27). Thus, a CaMKK2/CaMKI cascade regulates learning-induced neuronal cytoskeleton remodeling associated with memory formation.…”

Section: Camkk2 and Brain Functionsmentioning

confidence: 99%

See 3 more Smart Citations

Calcium/Calmodulin-dependent Protein Kinase Kinase 2: Roles in Signaling and Pathophysiology

Means

2012

Journal of Biological Chemistry

Self Cite

247

204

View full text Add to dashboard Cite

Section: Camkk2: Structure and Functionmentioning

confidence: 99%

Section: Camkk2: Structure and Functionmentioning

confidence: 99%

Section: Camkk2: Structure and Functionmentioning

confidence: 99%

Section: Camkk2 and Brain Functionsmentioning

confidence: 99%

See 2 more Smart Citations

Calcium/Calmodulin-dependent Protein Kinase Kinase 2: Roles in Signaling and Pathophysiology

Means

2012

Journal of Biological Chemistry

Self Cite

247

204

View full text Add to dashboard Cite

“…CaMKK2 activity is itself also highly regulated both by phosphorylation and by binding to calcium-calmodulin. Of the multiple phosphorylation sites within CaMKK2 some have been shown in cell lines to be dependent on the activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3) [5]. A number of autophosphorylation sites have also been identified within CaMKK2.…”

Section: Introductionmentioning

confidence: 99%

Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2

Gerner

Munack

Temmerman

et al. 2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

(2016). Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2. Biochemical and Biophysical Research Communications, 476(2) This manuscript is distributed under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited. General rightsCopyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In conclusion, the intrinsic fluorescent properties of STO-609 provide a great opportunity to utilise this drug to label the ATP-binding pocket and probe the impact of mutations and other regulatory modifications and interactions on the pocket. It is however clear that the number of phosphorylation sites on CaMKK2 will pose a challenge in studying the impact of phosphorylation on the pocket unless the field can develop approaches to control the spectrum of modifications that occur during recombinant protein expression in E. coli.

show abstract

IB4‐binding sensory neurons in the adult rat express a novel 3′ UTR‐extended isoform of CaMK4 that is associated with its localization to axons

Harrison

Flight

Gomes

et al. 2013

J of Comparative Neurology

View full text Add to dashboard Cite

Calcium/Calmodulin-dependent protein Kinase 4 (Gene and transcript: CaMK4; Protein: CaMKIV) is the nuclear effector of the Ca2+/Calmodulin Kinase (CaMK) pathway where it co-ordinates transcriptional responses. However, CaMKIV is present in the cytoplasm and axons of subpopulations of neurons, including some sensory neurons of the dorsal root ganglia (DRG), suggesting an extra-nuclear role for this protein. We observed that CaMKIV was expressed strongly in the cytoplasm and axons of a subpopulation of small diameter DRG neurons, most likely cutaneous nociceptors by virtue of their binding the isolectin IB4. In IB4+ spinal nerve axons, 20% of CaMKIV was co-localized with the endocytic marker Rab7 in axons that highly expressed CAM-Kinase-Kinase (CAMKK), an upstream activator of CaMKIV, suggesting a role for CaMKIV in signalling though signalling endosomes. Using fluorescent in situ hybridization (FISH) with riboprobes, we also observed that small diameter neurons expressed high levels of a novel 3' untranslated region (UTR) variant of CaMK4 mRNA. Using rapid amplification of cDNA ends (RACE), RT-PCR with gene-specific primers, and cDNA sequencing analyses we determined that the novel transcript contains an additional 10kb beyond the annotated gene terminus to a highly conserved alternate poly-adenylation site. qPCR analyses of fluorescent-activated cell sorted (FACS) DRG neurons confirmed that this 3'UTR-extended variant was preferentially expressed in IB4-binding neurons. Computational analyses of the 3'-UTR sequence predict that UTR-extension introduces consensus sites for RNA-binding proteins (RBPs) including the Embryonic Lethal Abnormal Vision (ELAV)/Hu family proteins. We consider the possible implications of axonal CaMKIV in the context of the unique properties of IB4-binding DRG neurons.

show abstract

Ca2+/Calmodulin-dependent Protein Kinase Kinase β Is Regulated by Multisite Phosphorylation

Cited by 61 publications

References 54 publications

Calcium/Calmodulin-dependent Protein Kinase Kinase 2: Roles in Signaling and Pathophysiology

Calcium/Calmodulin-dependent Protein Kinase Kinase 2: Roles in Signaling and Pathophysiology

Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2

IB4‐binding sensory neurons in the adult rat express a novel 3′ UTR‐extended isoform of CaMK4 that is associated with its localization to axons

Contact Info

Product

Resources

About