A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors

Samelson, Bret K.; Gore, Bryan B.; Whiting, Jennifer L.; Nygren, Patrick J.; Purkey, Alicia; Colledge, Marcie; Langeberg, Lorene K.; Dell’Acqua, Mark L.; Zweifel, Larry S.; Scott, John D.

doi:10.1074/jbc.m115.637470

Cited by 13 publications

(11 citation statements)

References 73 publications

(74 reference statements)

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“…Lastly, a proximity ligation assay (PLA) was used to pinpoint p766-Gravin association with either kinase during the cell cycle ( Figure 2E–H ). This approach combines antibody recognition with amplification of a DNA hetero-duplex to mark discrete protein–protein interaction pairs that reside within 40–60 nm of each other ( Samelson et al, 2015 ). Quantification of PLA puncta indicated that p766-Gravin/Aurora A sub-complexes was enhanced 3.86-fold during metaphase when compared to interphase cells ( Figure 2E,F ).…”

Section: Resultsmentioning

confidence: 99%

A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells

Hehnly

Canton

Bucko

et al. 2015

eLife

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Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin−/− mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division.DOI: http://dx.doi.org/10.7554/eLife.09384.001

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Section: Resultsmentioning

confidence: 99%

A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells

Hehnly

Canton

Bucko

et al. 2015

eLife

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“…Moreover, functional analyses reveal that loss of this anchoring protein promotes a redistribution of its enzyme binding partners including protein kinase A and calcineurin with concomitant changes in a variety of vital cellular processes including excitatory synaptic transmission, glucose homeostasis and vascular tone (13; 31; 41; 42). However, much less is known about the AKAP150-calcineurin interface in the heart (43–46).…”

Section: Resultsmentioning

confidence: 99%

AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction

Nieves‐Cintrón

Hirenallur-Shanthappa

Nygren

et al. 2016

Cellular Signalling

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The Ca2+-responsive phosphatase calcineurin/ protein phosphatase 2B dephosphorylates the transcription factor NFATc3. In the myocardium activation of NFATc3 down-regulates the expression of voltage-gated K+ (Kv) channels after myocardial infarction (MI). This prolongs action potential duration and increases the probability of arrhythmias. Although recent studies infer that calcineurin is activated by local and transient Ca2+ signals the molecular mechanism that underlies the process is unclear in ventricular myocytes. Here we test the hypothesis that sequestering of calcineurin to the sarcolemma of ventricular myocytes by the anchoring protein AKAP150 is required for acute activation of NFATc3 and the concomitant down-regulation of Kv channels following MI. Biochemical and cell based measurements resolve that approximately 0.2% of the total calcineurin activity in cardiomyocytes is associated with AKAP150. Electrophysiological analyses establish that formation of this AKAP150-calcineurin signaling dyad is essential for the activation of the phosphatase and the subsequent down-regulation of Kv channel currents following MI. Thus AKAP150-mediated targeting of calcineurin to sarcolemmal micro-domains in ventricular myocytes contributes to the local and acute gene remodeling events that lead to the down-regulation of Kv currents.

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“…They include cellular (protein inhibitors) and pharmacological inhibitors. Although numerous endogenous proteins may have potential to inhibit calcineurin or NFAT activities, only four are well-characterized: (i) A-kinase anchoring protein 79 (AKAP79), a scaffold protein that prevents calcineurin-substrate interactions [ 96 , 97 ]; (ii) calcineurin inhibitor (CAIN) or calcineurin-binding (CABIN) proteins, which block calcineurin activity [ 98 , 99 ]; (iii) calcineurin homologous protein (CHP); and (vi) modulatory calcineurin-interacting proteins (MCIP1–3), which prevent NFAT nuclear import by preventing its phosphorylation [ 94 , 100 – 103 ].…”

Section: Calcineurin/nfat Pathwaymentioning

confidence: 99%

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

Kipanyula

Kimaro

Etet

2016

Journal of Aging Research

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The ongoing epidemics of metabolic diseases and increase in the older population have increased the incidences of neurodegenerative diseases. Evidence from murine and cell line models has implicated calcineurin-nuclear factor of activated T-lymphocytes (NFAT) signaling pathway, a Ca2+/calmodulin-dependent major proinflammatory pathway, in the pathogenesis of these diseases. Neurotoxins such as amyloid-β, tau protein, and α-synuclein trigger abnormal calcineurin/NFAT signaling activities. Additionally increased activities of endogenous regulators of calcineurin like plasma membrane Ca2+-ATPase (PMCA) and regulator of calcineurin 1 (RCAN1) also cause neuronal and glial loss and related functional alterations, in neurodegenerative diseases, psychotic disorders, epilepsy, and traumatic brain and spinal cord injuries. Treatment with calcineurin/NFAT inhibitors induces some degree of neuroprotection and decreased reactive gliosis in the central and peripheral nervous system. In this paper, we summarize and discuss the current understanding of the roles of calcineurin/NFAT signaling in physiology and pathologies of the adult and developing nervous system, with an emphasis on recent reports and cutting-edge findings. Calcineurin/NFAT signaling is known for its critical roles in the developing and adult nervous system. Its role in physiological and pathological processes is still controversial. However, available data suggest that its beneficial and detrimental effects are context-dependent. In view of recent reports calcineurin/NFAT signaling is likely to serve as a potential therapeutic target for neurodegenerative diseases and conditions. This review further highlights the need to characterize better all factors determining the outcome of calcineurin/NFAT signaling in diseases and the downstream targets mediating the beneficial and detrimental effects.

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A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors

Cited by 13 publications

References 73 publications

A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells

A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells

AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

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