KSR2 Is a Calcineurin Substrate that Promotes ERK Cascade Activation in Response to Calcium Signals

Dougherty, M. K.; Ritt, Daniel A.; Zhou, Ming; Specht, Suzanne I.; Monson, Daniel M.; Veenstra, Timothy D.; Morrison, Deborah K.

doi:10.1016/j.molcel.2009.06.001

Cited by 115 publications

(131 citation statements)

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“…More recently a possible mechanism linking glucose, Ca 2+ and ERK activation has been elucidated. The protein phosphatase calcineurin selectively dephosphorylates kinase suppressor of Ras 2 (KSR2) in response to Ca 2+ signals, regulating KSR2 localisation and ERK scaffold activity [45].…”

Section: Discussionmentioning

confidence: 99%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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Aims/hypothesis Beta cell failure is caused by loss of cell mass, mostly by apoptosis, but also by simple dysfunction (decline of glucose-stimulated insulin secretion, downregulation of specific gene expression). Apoptosis and dysfunction are caused, at least in part, by lipoglucotoxicity. The mechanisms implicated are oxidative stress, increase in the hexosamine biosynthetic pathway (HBP) flux and endoplasmic reticulum (ER) stress. Oxidative stress plays a role in glucotoxicity-induced beta cell dedifferentiation, while glucotoxicity-induced ER stress has been mostly linked to beta cell apoptosis. We sought to clarify whether ER stress caused by increased HBP flux participates in a dedifferentiating response of beta cells, in the absence of relevant apoptosis. Methods We used INS-1E cells and murine islets. We analysed the unfolded protein response and the expression profile of beta cells by real-time RT-PCR and western blot. The signal transmission pathway elicited by ER stress was investigated by real-time RT-PCR and immunofluorescence. Results Glucosamine and high glucose induced ER stress, but did not decrease cell viability in INS-1E cells. ER stress caused dedifferentiation of beta cells, as shown by downregulation of beta cell markers and of the transcription factor, pancreatic and duodenal homeobox 1. Glucose-stimulated insulin secretion was inhibited. These effects were prevented by the chemical chaperone, 4-phenyl butyric acid. The extracellular signal-regulated kinase (ERK) signal transmission pathway was implicated, since its inhibition prevented the effects induced by glucosamine and high glucose. Conclusions/interpretation Glucotoxic ER stress dedifferentiates beta cells, in the absence of apoptosis, through a transcriptional response. These effects are mediated by the activation of ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

et al. 2011

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“…KSR1 may be most important as a scaffold due to its ability to bind simultaneously to components at each level of the MAPK cascade (MAP3K, MAP2K, and MAPK). Because signaling is diminished if it is expressed in excess of its binding partners, KSR1 fits the characteristics of a scaffold [27,30,32]. A functional catalytic lysine appears to be absent from KSR, unlike what we found in WNK protein kinases; in WNKs the catalytic lysine is not in the canonical position, but it is nearby in a distinct structural element [33].…”

Section: Kinase Suppressor Of Rasmentioning

confidence: 62%

“…KSR1 knockout mice have been generated and show no extreme abnormalities other than modestly impaired immune and neuronal signaling, suggesting a functional redundancy between KSR1 and KSR2 [36,37]. KSR2 shares 43% sequence identity with KSR1, which includes the conserved regions required to bind to the three members of the ERK1/2 cascade, and maintains the ability to regulate pathway activation in a concentration-dependent manner [32]. However, novel roles for KSR2 have been reported in metabolic pathways.…”

Section: Kinase Suppressor Of Rasmentioning

confidence: 99%

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Signal control through Raf: in sickness and in health

2011

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The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the prototype mammalian mitogenactivated protein kinase (MAPK) signaling cascade that regulates a number of processes, including proliferation, differentiation, survival, migration, stress responses and apoptosis. How this seemingly linear cascade is modulated to achieve a specific cellular function has been a main focus of the field. In this review, we describe new as well as old findings in the regulation of the ERK1/2 pathway in normal and disease states via MAP3Ks.

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“…[29][30][31] KSR1 and KSR2 bind to Raf, MEK, and ERK thereby controlling their phosphorylation and activation. 32,33 In C. elegans KSR1/2 have overlapping but also isotype-specific interactions and functions. 34 In mammalian cells, KSR1 is crucial for oncogenic Ras signaling by binding to Raf-1 and B-Raf, [35][36][37] whereas KSR2 recruits A-Raf rather than Raf-1 or B-Raf in response to TNFα.…”

mentioning

confidence: 99%

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

et al. 2016

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A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the MEK-ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. We recently identified A-Raf as a potent inhibitor of the proapoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities including head and neck, colon, and breast. Independent of kinase activity, A-Raf binds to MST2 thereby efficiently inhibiting apoptosis. Here, we show that the interaction of A-Raf with the MST2 pathway is regulated by subcellular compartmentalization. Although in proliferating normal cells and tumor cells A-Raf localizes to the mitochondria, differentiated non-carcinogenic cells of head and neck epithelia, which express A-Raf at the plasma membrane. The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis. Physiologically, A-Raf re-localizes to the plasma membrane upon epithelial differentiation in vivo. This re-distribution is regulated by the scaffold protein kinase suppressor of Ras 2 (KSR2). Downregulation of KSR2 during mammary epithelial cell differentiation or siRNA-mediated knockdown re-localizes A-Raf to the plasma membrane causing the release of MST2. By using the MCF7 cell differentiation system, we could demonstrate that overexpression of A-Raf in MCF7 cells, which induces differentiation. Our findings offer a new paradigm to understand how differential localization of Raf complexes affects diverse signaling functions in normal cells and carcinomas. A-Raf is a member of the Raf family of serine-threonine protein kinases, which comprises A-Raf, B-Raf, and Raf-1. Raf kinases are at the apex of the three-tiered Raf/MEK/ extracellular signal-regulated kinase (ERK) (mitogen-activated protein kinase (MAPK)) pathway regulating fundamental cellular functions, including differentiation, transformation, apoptosis, proliferation, and metabolism. 1,2 Activation of Ras GTPases at the cell membrane initiates Raf kinase activation and sequential phosphorylation and activation of the serinethreonine kinases MEK1/2 and ERK1/2. 3,4 In comparison to Raf-1 and B-Raf, A-Raf is only weakly activated by oncogenic H-Ras and Src 5 and is a poor MEK kinase, 5-8 which is due to unique non-conserved amino acid substitutions in the N-region. 9 Only recently, the first somatic oncogenic mutations of A-Raf were identified in lung adenocarcinomas 10 and Langerhans cell histiocytosis. 11,12 We recently showed that A-Raf and Raf-1, independent of their kinase activity, bind the proapoptotic mammalian sterile 20-like kinase (MST2) thereby suppressing MST2 activation and MST2-induced apoptosis. 13-17 MST2 employs several mechanisms to induce apoptosis including the transcriptional induction of PUMA, 14 a BH3 domain protein that causes mitochondrial depolarization and subsequent cell death. 18 Although Raf-1 counteracts MS...

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KSR2 Is a Calcineurin Substrate that Promotes ERK Cascade Activation in Response to Calcium Signals

Cited by 115 publications

References 46 publications

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

Signal control through Raf: in sickness and in health

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

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