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

Hehnly, Heidi; Canton, David A.; Bucko, Paula; Langeberg, Lorene K.; Ogier, Leah; Gelman, Irwin H.; Santana, Luis Fernando; Wordeman, Linda; Scott, John D.

doi:10.7554/elife.09384

Cited by 45 publications

(78 citation statements)

References 55 publications

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“…A-kinase anchoring proteins (AKAPs) are scaffolding proteins that regulate cellular cAMP responses by spatiotemporally coordinating PKA with target proteins specific to individual activation stimuli (27,28). AKAP12 (also called Gravin and SSeCKS) has been implicated in a wide range of cell functions, including tumor suppression (29–31), cytoskeletal architecture (32,33), β 2 -adrenergic receptor desensitization/resensitization (34,35) and cell cycle regulation (36–38). AKAP12 activities have been described at the plasma membrane, the cell periphery and at perinuclear regions of the cytoplasm (28).…”

Section: Introductionmentioning

confidence: 99%

Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Jarrett

Horrell

D’Orazio

2016

Nucleic Acids Research

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Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5′ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.

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Section: Introductionmentioning

confidence: 99%

Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Jarrett

Horrell

D’Orazio

2016

Nucleic Acids Research

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“…When grown in Matrigel, mIMCD3 cells form 3D polarized spheroids (31). This offers an elegant model system that is amenable to microscopic analysis of the actin cytoskeleton (31,32). To determine whether loss of AKAP220 impacts actin organization, spheroids were grown from WT or AKAP220-null cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

Whiting

Ogier

Forbush

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Filtration through the kidney eliminates toxins, manages electrolyte balance, and controls water homeostasis. Reabsorption of water from the luminal fluid of the nephron occurs through aquaporin-2 (AQP2) water pores in principal cells that line the kidney-collecting duct. This vital process is impeded by formation of an "actin barrier" that obstructs the passive transit of AQP2 to the plasma membrane. Bidirectional control of AQP2 trafficking is managed by hormones and signaling enzymes. We have discovered that vasopressin-independent facets of this homeostatic mechanism are under the control of A-Kinase Anchoring Protein 220 (AKAP220; product of the Akap11 gene). CRISPR/Cas9 gene editing and imaging approaches show that loss of AKAP220 disrupts apical actin networks in organoid cultures. Similar defects are evident in tissue sections from AKAP220-KO mice. Biochemical analysis of AKAP220-null kidney extracts detected reduced levels of active RhoA GTPase, a well-known modulator of the actin cytoskeleton. Fluorescent imaging of kidney sections from these genetically modified mice revealed that RhoA and AQP2 accumulate at the apical surface of the collecting duct. Consequently, these animals are unable to appropriately dilute urine in response to overhydration. We propose that membrane-proximal signaling complexes constrained by AKAP220 impact the actin barrier dynamics and AQP2 trafficking to ensure water homeostasis. yet only approximately 1.5 L of urine is excreted. The majority of this water is reabsorbed from the luminal fluid of the nephron (1). Regulated water reabsorption in response to dehydration occurs through aquaporin-2 (AQP2) water pores in the principal cells of the collecting duct (2). This is stimulated by the hormone arginine vasopressin (AVP). Vasopressin induces PKA phosphorylation of serine 256 on AQP2 and stimulates its translocation from intracellular vesicles to the apical membranes of cells lining the collecting ducts. Reabsorption of water through the kidney preserves fluid balance and results in more concentrated urine (3, 4). Conversely, when an animal ingests excess water, decreased plasma osmolality inhibits vasopressin release, and AQP2 is recovered from the apical membrane by endocytosis. This renders the collecting duct impermeable to water, thereby diverting excess water through the ureter to the bladder.Not surprisingly, defects in AQP2 trafficking have pathophysiological outcomes. For example, nephrogenic diabetes insipidus (NDI) is associated with impaired vasopressin signaling to AQP2 (5-8). Symptoms include excessive thirst, excretion of a large volume of dilute urine, and electrolyte imbalances, including hypernatremia (1, 5). Hereditary forms of this disease appear in patients with inactivating mutations in the V2 vasopressin receptor (V2R) or AQP2 (9-12). Thus, understanding the molecular mechanisms that govern bidirectional control of AQP2 location may lead to new therapeutic approaches for the treatment of NDI.Although the enzymes and effector proteins that govern AQP2 in...

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“…However, it is unknown how all these molecules act in concert to correctly position the spindle along the division axis. We do know that if we un‐couple PLK1 from its scaffold Gravin, increased phosphorylation of its downstream substrate CEP215 occurs, which is associated with a loss of astral microtubules and corresponding spindle positioning defects (Colicino et al, ; Hehnly et al, ). It is unknown, though, where the mother centriole appendage protein cenexin, or the PCM proteins pericentrin and MCPH2 fits into this possible pathway.…”

Section: Role Of Plk1 At Centrosomes Kinetochores and Cytokinetic Mmentioning

confidence: 99%

“…This will allow centrosome‐ or kinetochore‐tethered PLK1 to be inhibited using a purine analogue or wild‐type PLK1 using a common PLK1 inhibitor (BI 2536) in order to tease out the consequences of PLK1 at the mitotic centrosomes versus the kinetochores. In addition, just as with the kinetochore (Lera et al, ), PLK1 as could be tethered to subcompartments of the centrosome, where it is known to have a specific function (e.g., PCM, centriole, or mother centriole appendages) (Colicino et al, ; Hehnly et al, ; Lee & Rhee, ; Soung et al, ). These studies could elucidate whether PLK1 operates in pools within the centrosome, as it seems to operate at the kinetochore (Lera et al, ).…”

Section: Role Of Plk1 At Centrosomes Kinetochores and Cytokinetic Mmentioning

confidence: 99%

“…(Choi, Liu, Sze, Dai, & Qi, ; Doxsey, Steln, Evans, Calarco, & Kirschnefi, ; Fabbro et al, ; Kolobova et al, ; Zimmerman, Sillibourne, Rosa, & Doxsey, ). The recruitment of these components require activated mitotic signaling cascades involving the mitotic kinases Aurora A, polo‐like kinases (PLKs), and cyclin‐dependent kinase 1 (CDK1) to name a few (Bruinsma et al, ; Hehnly et al, ; Lee et al, ; Sanhaji et al, ; Thomas et al, ). One kinase that seems to be at the center of this process from a single cell eukaryote to a multi‐cellular vertebrate is polo‐like kinase 1 (PLK1).…”

Section: Introductionmentioning

confidence: 99%

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Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

Colicino

Hehnly

2018

Cytoskeleton

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During cell division, duplicated genetic material is separated into two distinct daughter cells. This process is essential for initial tissue formation during development and to maintain tissue integrity throughout an organism's lifetime. To ensure the efficacy and efficiency of this process, the cell employs a variety of regulatory and signaling proteins that function as mitotic regulators and checkpoint proteins. One vital mitotic regulator is polo‐like kinase 1 (PLK1), a highly conserved member of the polo‐like kinase family. Unique from its paralogues, it functions specifically during mitosis as a regulator of cell division. PLK1 is spatially and temporally enriched at three distinct subcellular locales; the mitotic centrosomes, kinetochores, and the cytokinetic midbody. These localization patterns allow PLK1 to phosphorylate specific downstream targets to regulate mitosis. In this review, we will explore how polo‐like kinases were originally discovered and diverged into the five paralogues (PLK1‐5) in mammals. We will then focus specifically on the most conserved, PLK1, where we will discuss what is known about how its activity is modulated, its role during the cell cycle, and new, innovative tools that have been developed to examine its function and interactions in cells.

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

Cited by 45 publications

References 55 publications

Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

Regulating a key mitotic regulator, polo‐like kinase 1 (PLK1)

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