Activation of 3-Phosphoinositide-dependent Kinase 1 (PDK1) and Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1) by Short-chain Sphingolipid C4-ceramide Rescues the Trafficking Defect of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR)

Caohuy, Hung; Yang, Qingfeng; Eudy, Yvonne; Ha, Thien-An; Xu, Andrew E.; Glover, M L; Frizzell, Raymond A.; Jozwik, Catherine; Pollard, Harvey B.

doi:10.1074/jbc.m114.598649

Cited by 28 publications

(19 citation statements)

References 57 publications

(65 reference statements)

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“…On the other hand, a large amount of data from independent groups strongly supports the notion that the E3 ubiquitin ligase NEDD4L, which regulates internalization and turnover of a number of membrane proteins, can be negatively regulated by both AKT and SGK1 (Boehmer, Okur, Setiawan, Broer, & Lang, 2003; Caohuy et al, 2014; Lee, Dinudom, Sanchez-Perez, Kumar, & Cook, 2007), although gain- and loss-of-function experiments support SGK1 as more relevant for this function (Andersen et al, 2013). …”

Section: Akt and Sgk1: Target Overlap And Selectivitymentioning

confidence: 97%

Sgk1

Cristofano

2017

Current Topics in Developmental Biology

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Activation of the PI3K pathway is central to a variety of physiological and pathological processes. In these contexts, AKT is classically considered the de facto mediator of PI3K-dependent signaling. However, in recent years, accumulating data point to the existence of additional effectors of PI3K activity, parallel to and independent of AKT, that play critical and unique roles in mediating different developmental, homeostatic, and pathological processes. In this review, I summarize and discuss our current understanding of the function of the serine/threonine kinase SGK1 as a downstream effector of PI3K, and try to separate targets and pathways validated as uniquely SGK1-dependent from those shared with AKT.

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Section: Akt and Sgk1: Target Overlap And Selectivitymentioning

confidence: 97%

Sgk1

Cristofano

2017

Current Topics in Developmental Biology

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“…PDK1 has also been suggested to play a role in fibroblast-mediated pulmonary fibrosis, acting as a secondary messenger to activate Akt upon TGFβ-mediated PI3K activation (27). However, PDK1 activation has also been demonstrated to be protective, when in conjunction with serum/glucocorticoid-induced protein kinase 1, in an in vitro cellular model (28). Given the complexity of the PI3K-PDK1-AKT pathway and the diverse range of mechanisms that it modulates, more research is required to clarify how this pathway modulates FA formation during health and injury.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteome profiling provides insight into the mechanisms of ventilator‑induced lung injury

et al. 2020

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The incidence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common health problem in the clinic and is projected to increase in prevalence in the future. Mechanical ventilation is commonly used to provide respiratory support and has become indispensable in emergency and critical medicine. However, ventilator use can result in lung tissue damage, collectively termed ventilator-induced lung injury (VILI). In the present study, phosphoprotein profiling of blood and tissue samples from ventilated and non-ventilated mice was performed and key changes in protein levels and cell signaling during VILI were identified. Activation of the PI3K/AKT and mitogen activated protein kinase signaling pathways, in addition to changes in expression of cancer, inflammatory and cell-death related proteins were detected in response to mechanical ventilation. Focal adhesion-related protein levels and signaling pathways were also significantly altered in an injury model compared with control. VILI can affect patient mortality in ALI and ARDS cases, and no targeted treatment options currently exist. Identifying biomarkers and understanding the signaling pathways associated with VILI is critical for the development of future therapies.

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“…These interactions are sensitive to multiple signalling pathways 110 that likely impact both normal and perhaps differentially, CFFL. Moreover, CFTR interacts with and is regulated by, in unknown ways, the cytoskeleton 95 , numerous folding and trafficking components 2–4 (Pankow et.…”

Section: Cf Hallmark 2: Making Connections-the Cf Social Interaction mentioning

confidence: 99%

Hallmarks of therapeutic management of the cystic fibrosis functional landscape

Amaral

Balch

2015

Journal of Cystic Fibrosis

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The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein does not operate in isolation, rather in a dynamic network of interacting components that impact its synthesis, folding, stability, intracellular location and function, referred to herein as the ‘CFTR Functional Landscape (CFFL)’. For the prominent F508del mutation, many of these interactors are deeply connected to a protein fold management system, the proteostasis network (PN). However, CF encompasses an additional 2000 CFTR variants distributed along its entire coding sequence (referred to as CFTR2), and each variant contributes a differential liability to PN management of CFTR and to a protein ‘Social Network’ (SN) that directs the probability of the (patho)physiologic events that impact ion transport in each cell, tissue and patient in health and disease. Recognition of the importance of the PN and SN in driving the unique patient CFFL leading to disease highlights the importance of precision medicine in therapeutic management of disease progression. We take the view herein that it is not CFTR, rather the PN/SN, and their impact on the CFFL, that are the key physiologic forces driving onset and clinical progression of CF. We posit that a deep understanding of each patients PN/SN gained by merging genomic, proteomic (mass spectrometry (MS)), and high-content microscopy (HCM) technologies in the context of novel network learning algorithms will lead to a paradigm shift in CF clinical management. This should allow for generation of new classes of patient specific PN/SN directed therapeutics for personalized management of the CFFL in the clinic.

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Activation of 3-Phosphoinositide-dependent Kinase 1 (PDK1) and Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1) by Short-chain Sphingolipid C4-ceramide Rescues the Trafficking Defect of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR)

Cited by 28 publications

References 57 publications

Sgk1

Sgk1

Phosphoproteome profiling provides insight into the mechanisms of ventilator‑induced lung injury

Hallmarks of therapeutic management of the cystic fibrosis functional landscape

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