Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter

Kajimoto, Tetsuya; Caliman, Alisha D.; Tobias, Irene S.; Okada, Taro; Pilo, Caila A.; Van, An-Angela N.; McCammon, J. Andrew; Nakamura, Shun‐ichi; Newton, Alexandra C.

doi:10.1126/scisignal.aat6662

Cited by 47 publications

(37 citation statements)

References 71 publications

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“…How many regulatory processes are altered by fumonisins, and which play the most important roles in disease? In this regard, one must be mindful that new connections between SL and cell regulation are still being discovered and some might be pertinent to fumonisin action, such as: the activation of atypical protein kinase Cs (aPKCs) (PKC and PKC/, which are involved in diverse cellular functions, and can serve as oncogenes or tumor suppressors) by S1P and Sa1P (46); the activation of SNAI2 (a transcriptional regulator of the epithelial to mesenchymal transition) by S1P (47) and its suppression by Cer (48); and others (see Supplement B).…”

Section: Some Of the Unknowns Of Fumonisin Action (And Perspectives Fmentioning

confidence: 99%

Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

Riley

Merrill

2019

Journal of Lipid Research

110

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Fumonisins are mycotoxins that cause diseases of plants and, when consumed by animals, can damage liver, kidney, lung, brain, and other organs, alter immune function, and cause developmental defects and cancer. They structurally resemble sphingolipids (SLs), and studies nearly 30 years ago discovered that the most prevalent fumonisin [fumonisin B 1 (FB 1)] potently inhibits ceramide synthases (CerSs), enzymes that use fatty acyl-CoAs to N-acylate sphinganine (Sa), sphingosine (So), and other sphingoid bases. CerS inhibition by FB 1 triggers a "perfect storm" of perturbations in structural and signaling SLs that include: reduced formation of dihydroceramides, ceramides, and complex SLs; elevated Sa and So and their 1-phosphates, novel 1-deoxy-sphingoid bases; and alteration of additional lipid metabolites from interrelated pathways. Moreover, because the initial enzyme of sphingoid base biosynthesis remains active (sometimes with increased activity), the impact is multiplied by the continued production of damaging metabolites. Evidence from many studies, including characterization of knockout mice for specific CerSs and analyses of human blood (which found that FB 1 intake is associated with elevated Sa 1-phosphate), has consistently pointed to CerS as the proximate target of FB 1. It is also apparent that the changes in multiple bioactive lipids and related biologic processes account for the ensuing spectrum of animal and plant disease. Thus, the diseases caused by fumonisins can be categorized as "sphingolipidoses" (in these cases, due to defective SL biosynthesis), and the lessons learned about the consequences of CerS inhibition should be borne in mind when contemplating other naturally occurring and synthetic compounds (and genetic manipulations) that interfere with SL metabolism.-Riley, R. T., and A. H. Merrill, Jr. Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease.

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Section: Some Of the Unknowns Of Fumonisin Action (And Perspectives Fmentioning

confidence: 99%

Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

Riley

Merrill

2019

Journal of Lipid Research

110

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“…In contrast, S1P has opposing roles in enhancing cell survival and proliferation, as well as other roles in stimulating cell migration, angiogenesis and inflammation [105][106][107]. These effects of S1P, which are mediated through five S1P-selective G-protein coupled receptors, named S1P 1-5 [92][93][94][95][108][109][110], as well as via intracellular targets such as peroxisome proliferator-activated receptor (PPAR)γ [111], telomerase [112], histone deacetylases 1 and 2 [113] and atypical protein kinase C [114]. The cellular balance and localization of these sphingolipids contributes to the determination of cell fate; therefore, disruption of this 'sphingolipid rheostat' may lead to disease development, progression and chemotherapeutic resistance of malignancies including GBM [94,105,115,116].…”

Section: Sphingolipid Biosynthesis and Metabolismmentioning

confidence: 99%

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

Tea

Poonnoose

Pitson

2020

Cancers

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Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.

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“…In addition, recent studies suggest the binding of S1P to the histone deacetylases 1/ 2 (HDACs) [59], human telomerase [60], PARPγ [61] and atypical protein kinase C [62]. Moreover, S1P specifically interacts with the N-terminal domain of the heat shock proteins GRP94 and HSP90α [63].…”

Section: S1p/s1pr Signalingmentioning

confidence: 99%

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

Meacci

Garcia‐Gil

2019

IJMS

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The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot–Marie–Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.

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Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter

Cited by 47 publications

References 71 publications

Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

Ceramide synthase inhibition by fumonisins: a perfect storm of perturbed sphingolipid metabolism, signaling, and disease

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

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