Mitochondrial AKAP1 supports mTOR pathway and tumor growth

Rinaldi, Laura; Sepe, Maria; Donne, Rossella Delle; Conte, Kristel; Arcella, Antonietta; Borzacchiello, Domenica; Amente, Stefano; Vita, Fernanda De; Porpora, Monia; Garbi, Corrado; Oliva, Maria Antonietta; Procaccini, Claudio; Faicchia, Deriggio; Matarese, Giuseppe; Marino, Federica Zito; Rocco, Gaetano; Pignatiello, Sara; Franco, Renato; Insabato, Luigi; Majello, Barbara; Feliciello, Antonio

doi:10.1038/cddis.2017.241

Cited by 47 publications

(50 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…But, one can anticipate that the scaffolding and organization of these molecular pathways will be critical to this integration. This potential has been noted with AKAP1, which plays a crucial role in the integration of PKA and mTOR signaling modules . It is likely that similar mechanisms exist for other signaling proteins to balance mitochondrial form and function in an everchanging cellular environment.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 85%

“…The localization of mTOR places the kinase near other regulators including AMPK making mTOR an emerging regulator of mitochondria function capable of responding to changes in redox status and bioenergetics shifts. Alternatively, mTOR may have a role in OMM signaling through interplay with AKAP‐1, wherein mitochondrial PKA signaling may influence mTOR activity . It is clear that mTOR signaling is highly integrated with mitochondria physiology …”

Section: Other Kinases Associated With Ommmentioning

confidence: 99%

“…Alternatively, mTOR may have a role in OMM signaling through interplay with AKAP-1, wherein mitochondrial PKA signaling may influence mTOR activity. 217 It is clear that mTOR signaling is highly integrated with mitochondria physiology. 212 Thus, the kinases presented above may only be a modest sampling of the cascades present on the mitochondrial surface.…”

Section: Mammalian Target Of Rapamycin (Mtor)mentioning

confidence: 99%

“…This potential has been noted with AKAP1, which plays a crucial role in the integration of PKA and mTOR signaling modules. 217 It is likely that similar mechanisms exist for other signaling proteins to balance mitochondrial form and function in an everchanging cellular environment. Research oriented around these distinct interactions will be critical to understanding the complex regulation of mitochondrial function and dysfunction in disease pathogenesis, and this scenario also highlights the need to consider therapeutic regimens that impair detrimental events while restoring beneficial signaling pathways on the OMM.…”

Section: Con Clud Ing Remark S and Future Direc Tionsmentioning

confidence: 99%

See 3 more Smart Citations

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

View full text Add to dashboard Cite

Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

show abstract

Section: Concluding Remarks and Future Directionsmentioning

confidence: 85%

Section: Other Kinases Associated With Ommmentioning

confidence: 99%

Section: Mammalian Target Of Rapamycin (Mtor)mentioning

confidence: 99%

Section: Con Clud Ing Remark S and Future Direc Tionsmentioning

confidence: 99%

See 2 more Smart Citations

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

View full text Add to dashboard Cite

show abstract

“…To further explore the cellular state properties that have the strongest unique impact on each response node, we started with the response markers pERK and pMTOR, which are well-characterized kinases that have been linked to different properties of the cellular state 35,36,39,40 . Plotting their single-cell abundances after 5 min of exposure to 100ng/ml EGF reveals strong correlation 0.82 .…”

Section: Non-redundant Sensing Of Cellular Statementioning

confidence: 99%

Cellular state determines the multimodal signaling response of single cells

Kramer

Pelkmans

2019

Preprint

View full text Add to dashboard Cite

Numerous fundamental biological processes require individual cells to correctly interpret and accurately respond to incoming cues. How intracellular signaling networks achieve the integration of complex information from various contexts remains unclear. Here we quantify epidermal growth factor-induced heterogeneous activation of multiple signaling proteins, as well as cellular state markers, in the same single cells across multiple spatial scales. We find that the acute response of each node in a signaling network is tightly coupled to the cellular state in a partially non-redundant manner. This generates a multimodal response that senses the diversity of cellular states better than any individual response alone and allows individual cells to accurately place growth factor concentration in the context of their cellular state. We propose that the non-redundant multimodal property of signaling networks in mammalian cells underlies specific and contextaware cellular decision making in a multicellular setting.State-dependent decision making by individual cells is a hallmark of multicellular life. This is prominently exemplified in embryonic development, where spatial and temporal cues determine cellular fate, driving the emergence of complex multicellular structures which consist of multiple cell types with highly diversified patterns of gene expression 1,2,3,4,5,6 . Integration of spatial cues and cellular context is also observed in vitro.In intestinal organoids, symmetry breaking is determined by the mechanical context of individual cells 7 , while cell fates in pluripotent stem cell populations are determined by differences in cell density and distance to colony edge 8,9 . Also in tissue culture cells, cellular activities and gene expression show predictable adaptation to heterogeneous microenvironments and cellular states 10,11,12,13,14 . The fidelity of these decisions relies on information processing by signaling networks 15,16,17,18,19 . This involves the concomitant activation of multiple connected signaling nodes composed of kinases, phosphatases, small GTPases, and effector proteins. The flow of information through these signaling nodes is highly variable between individual cells, even when cells are genetically identical and exposed to identical amounts of cytokine or growth factor 16,20,21 .As a result, cell populations can exhibit broad distributions of single-cell signaling responses 16,22,23,24,25 .Although different concentrations of cytokine or growth factor indeed elicit distinct mean response values, an accurate measurement of the exact concentration is impossible for individual cells because the full response distributions overlap considerably 20,25 ( Fig. 1a). It therefore remains largely unclear how individual cells are able to accurately integrate the complexity of variable extra-and intracellular information and convert this into a specific, context-aware response with the remarkable and reproducible accuracy necessary to sustain multicellular life.One mechanism is based on temporal integrati...

show abstract