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Scaffolding During the Cell Cycle by A-Kinase Anchoring Proteins

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Scaffolding During the Cell Cycle by A-Kinase Anchoring Proteins Pflugers Arch - Eur J Physiol DOI 10.1007/s00424-015-1718-0 INVITED REVIEW Scaffolding during the cell cycle by A-kinase anchoring proteins B. Han1,2 & W. J. Poppinga1,2 & M. Schmidt1,2 Received: 12 May 2015 /Revised: 28 June 2015 /Accepted: 1 July 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Cell division relies on coordinated regulation of the specific AKAP subset in relation to diseases with focus on a cell cycle. A process including a well-defined series of strictly diverse subset of cancer. regulated molecular mechanisms involving cyclin-dependent kinases, retinoblastoma protein, and polo-like kinases. Dys- Keywords AKAPs . Scaffolding . Cell cycle . Proliferation . functions in cell cycle regulation are associated with disease Cancer such as cancer, diabetes, and neurodegeneration. Compart- mentalization of cellular signaling is a common strategy used to ensure the accuracy and efficiency of cellular responses. Introduction Compartmentalization of intracellular signaling is maintained by scaffolding proteins, such as A-kinase anchoring proteins The growth of organisms is driven by cell division which (AKAPs). AKAPs are characterized by their ability to anchor relies on coordinated regulation of phases in cell cycle [4]. the regulatory subunits of protein kinase A (PKA), and there- When the cell is quiescent, it remains in the G1 phase; how- by achieve guidance to different cellular locations via various ever, on initiation of cell division, it progresses into the S targeting domains. Next to PKA, AKAPs also associate with phase, during which DNA replication occurs, followed by a several other signaling elements including receptors, ion chan- separation of sister chromatids during the M phase, which in nels, protein kinases, phosphatases, small GTPases, and phos- turn is again separated in the pro-, meta-, ana-, and telophase, phodiesterases. Taking the amount of possible AKAP signal- followed by cytokinesis where the actual cell division occurs. ing complexes and their diverse localization into account, it is A series of strictly regulated molecular mechanisms are re- rational to believe that such AKAP-based complexes regulate quired to maintain the progression of the cell cycle including several critical cellular events of the cell cycle. In fact, several cyclin-dependent kinases (CDKs), retinoblastoma protein AKAPs are assigned as tumor suppressors due to their vital (Rb), and polo-like kinases (Plks) [10, 24, 117]. In accor- roles in cell cycle regulation. Here, we first briefly discuss the dance, several diseases have been found to directly or indi- most important players of cell cycle progression. After that, rectly relate to a defective regulation of the cell cycle, such as we will review our recent knowledge of AKAPs linked to the cancer, diabetes, and neurodegeneration [93, 115]. regulation and progression of the cell cycle, with special focus Importantly, over the past years, it is accepted that compart- on AKAP12, AKAP8, and Ezrin. At last, we will discuss this mentalization of cellular signaling is a common strategy used to ensure the accuracy and efficiency of cellular responses [67]. Cellular compartmentalization of proteins involved in * B. Han signal transduction is maintained by scaffolding proteins, such [email protected] as A-kinase anchoring proteins (AKAPs), which are able to orientate a diverse subset of signaling effectors, such as pro- 1 Department of Molecular Pharmacology, University of Groningen, tein kinase A (PKA), extracellular-signal-regulated kinase Groningen, The Netherlands (ERK), and cyclins, towards selected substrates in specific 2 Groningen Research Institute for Asthma and COPD, GRIAC, cellular microdomains [80, 91, 109]. AKAPs are characterized Groningen, The Netherlands by their ability to anchor the regulatory subunits of PKA via a Pflugers Arch - Eur J Physiol conserved short α helical structure, and thereby achieve guid- functions as an E3 ubiquitin ligase to inhibit the progression ance to different cellular locations via various targeting do- into the M phase by decreasing the levels of cyclin B [99]. In mains. PKA is a cAMP-dependent serine/threonine kinase addition, the M phase is regulated by a series of complexes or and a very important player in many different cellular path- enzymes that control chromosome segregation and condensa- ways. The involvement of PKA in the cell cycle progression is tion (e.g., condensin, histone H3, and Aurora B kinase) [42, diversely regulated in different cell types. In Xenopus embry- 58, 108]. In Fig. 1, the interactions between AKAPs and sev- onic cells, PKA activity is low during the M phase but in- eral key players in cell cycle regulation are summarized. creases during M/G1 transition, [36, 37], whereas in the hu- man cancer cell line HeLa, PKA activity is increased during the M phase [104]. PKA negatively regulates the cell cycle AKAP12 progression upon activation of the small GTPase Rap1 and subsequent sequestration of Ras/MEK/ERk [22, 89]. Inhibi- AKAP12, originally called Gravin or AKAP250, was first tion of the cell cycle progression by PKA can also be achieved recognized as an autoantigen in serum from myasthenia gravis upon upregulation of the CDK inhibitor p27Kip1 [46]. patients [35]. Later, AKAP12 was found orthologous to a Next to PKA, AKAPs also associate with several other rodent protein, the Src-suppressed C Kinase Substrate signaling elements including receptors, ion channels, protein (SSeCKS) [62]. Since its discovery as an AKAP [73], kinases, phosphatases, small GTPases, and phosphodiester- AKAP12 is probably one of the most studied AKAPs in the ases [23, 80, 91]. Until now, over 50 members of the AKAP cell cycle regulation [34]. Several reports indicate that family have been identified, and each AKAP can form a AKAP12 generally regulates the cell cycle upon engagement unique signaling complex in different microdomains in the of distinct cell cycle phases: (1) acting as a negative regulator cells [29, 80, 91, 103]. With the large variety of AKAP sig- during inappropriate cell cycle progression; (2) helping to fa- naling complexes at many different locations inside the cell, it cilitate mitosis and cytokinesis [1, 73]. is feasible that such AKAP-based complexes regulate several critical cellular events of the cell cycle. In fact, several AKAPs are assigned as tumor suppressors due to their vital roles in cell AKAP12 as a negative regulator of the G1/S transition cycle regulation. Although the function of AKAP-PKA interactions in the AKAP12 regulates the cell cycle by reducing cyclin D1 ex- cell cycle is not well understood, the role of some AKAPs pression presumably mediated via inhibition of ERK [16, 82, being unveiled and will be described in this review. Here, 97, 105]. For example, Lin et al. reported in NIH 3T3 cells that we first briefly discuss the most important players of cell cycle induction of AKAP12 expression by tetracycline suppressed progression. After that, we will review our recent knowledge ERK2-dependent cyclin D1 expression and Rb phosphoryla- of AKAPs linked to the regulation and progression of the cell tion, effects that coincided with a G1 arrest [60]. Conversely, cycle, with special focus on AKAP12, AKAP8, and Ezrin. In knockdown of AKAP12 in a C6 rat glioma cells reversed the final section, we will discuss more about AKAP12 and dexamethasone-induced growth arrest, which was associated Ezrin in relation to disease. with elevated phosphorylation of ERK1/2 and expression of cyclin D1 [63]. Regulation of ERK might be mediated by controlling Src-focal adhesion kinase (FAK) complexes. Players of cell cycle regulation AKAP12 sequesters Src through direct binding [61, 95], thereby disengaging Src-FAK complexes away from ERK The cell cycle is controlled by the activity of CDKs, which in [1, 34]. Besides affecting the expression of cyclin D1, turn are controlled by cyclins such as cyclin D/E [112]. Ex- AKAP12 also sequesters cyclin D1, and thereby inhibits its posing cells to growth factors will elevate the amount of nuclear translocation. In AKAP12-overexpressing NIH 3T3 cyclins e.g., cyclin D1 in the cell through the Ras/Raf/MEK/ cells, the majority of cyclin D1 co-localized with AKAP12 ERK signaling cascade, [16, 76, 82], which can combine with in the cytoplasm, and nuclear cyclin D1 was reduced by about pre-existing CDKs to activate or inactivate target proteins, 70 % compared to controls [60]. In agreement, Burnworth such as Rb, to orchestrate the entry into the different phases et al. showed that cell-cell contact-induced AKAP12 expres- of the cell cycle [74]. The activity of cyclin-CDK complexes sion sequesters cyclin D1 and prevents its nuclear transloca- is tightly controlled, as check points, to fine-tune the cell cy- tion, resulting in growth arrest of glomerular parietal epithelial cle. For example, Plk1 activates cyclin B-CDK1 complex, cells [12]. AKAP12-mediated cyclin D1 sequestration is during the prophase to initiate the G2/M transition [100, inhibited by protein kinase C (PKC) phosphorylation of 101]. In addition, also the degradation of cyclins by AKAP12 [59] and short-term activation of PKC induced nu- ubiquitination allows cells to enter a next phase of the cell clear translocation of cyclin D1 even under AKAP12- cycle. For example, human enhancer of invasion 10 (HEI10) overexpression (Fig. 1)[60]. Pflugers Arch - Eur J Physiol Fig. 1 A-kinase anchoring proteins regulate the cell cycle by spatial and a multivalent platform to anchoring different signaling elements during temporal interaction with several key players. With the initiation of the cell cycle regulation. AKAP8 helps to recruit MCM2 to DNA and pro- G1 phase, cyclin-CDK signaling is crucially mediated by several AKAPs, motes thereby its replication during S phase. In the presence of growth most notably AKAP5, AKAP8, and AKAP12. AKAPs can mediate this factors, AKAP8 localizes to ERK-induced RSK1 in the nucleus to sub- by controlling either the expression, nuclear translocation, or activity of sequently induce cell proliferation.
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