A CC-SAM, for Coiled Coil–Sterile α Motif, Domain Targets the Scaffold KSR-1 to Specific Sites in the Plasma Membrane

Koveal, Dorothy; Schuh-Nuhfer, Natasha; Ritt, Daniel A.; Page, Rebecca; Morrison, Deborah K.; Peti, Wolfgang

doi:10.1126/scisignal.2003289

Cited by 32 publications

(41 citation statements)

References 46 publications

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“…Distribution to selected subcellular domains is required for the spatial and temporal restriction of the activity of signaling modules, as exemplified by the nucleocytoplasmic shuttling of both the yeast Ste5p and mammalian β-arrestin (Mahanty et al, 1999; Wang et al, 2003), or the tethering of KSR to the plasma membrane (Zhou et al, 2002; Ory and Morrison, 2004; Koveal et al, 2012). …”

Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

116

104

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The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

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Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

116

104

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“…PP2A). Recently, MAPK scaffolds (e.g., KSR) have also been shown to play a key role in modulating the strength and duration of MAPK activation . A comprehensive understanding of how the activity of MAPKs is finely controlled by MAPK regulatory proteins can only be obtained by understanding how these proteins interact at a molecular level.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of MAP kinase regulation

2013

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Mitogen-activated protein kinases (MAPKs; ERK1/2, p38, JNK, and ERK5) have evolved to transduce environmental and developmental signals (growth factors, stress) into adaptive and programmed responses (differentiation, inflammation, apoptosis). Almost 20 years ago, it was discovered that MAPKs contain a docking site in the C-terminal lobe that binds a conserved 13-16 amino acid sequence known as the D-or KIM-motif (kinase interaction motif). Recent crystal structures of MAPK:KIM-peptide complexes are leading to a precise understanding of how KIM sequences contribute to MAPK selectivity. In addition, new crystal and especially NMR studies are revealing how residues outside the canonical KIM motif interact with specific MAPKs and contribute further to MAPK selectivity and signaling pathway fidelity. In this review, we focus on these recent studies, with an emphasis on the use of NMR spectroscopy, isothermal titration calorimetry and small angle X-ray scattering to investigate these processes.

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“…Therefore, it is possible that the interaction between KSR1 and caveolin-1 occurs before KSR1 adapts a fully closed conformation. These data raise the possibility that caveolin-1 plays a role in the recruitment of KSR1 to caveolae, while the critical step in the localization of KSR1 to the plasma membrane is strictly regulated by the CC-SAM motif and the CA3 domain of KSR1 (44). Detailed structural studies between the CBM of proteins and the scaffolding domain of caveolin-1 will conclusively determine the extent to which the CBM directly mediates the caveolin-1 interaction.…”

Section: Discussionmentioning

confidence: 94%

“…KSR1 localizes to the plasma membrane upon activation of the Raf/MEK/ERK kinase cascade (43). An atypical C1 domain mediates the interaction between KSR1 and the plasma membrane, and KSR1 is directed to specific sites at the plasma membrane by a domain composed of a coiled-coiled (CC) and a sterile ␣ motif (SAM) module (44,45). Since KSR1 organizes members of the Raf/MEK/ERK kinase cascade at the plasma membrane (43), we hypothesized that KSR1 localized to caveolae upon activation of the Raf/MEK/ERK kinase cascade.…”

Section: Resultsmentioning

confidence: 99%

Caveolin-1 Is Required for Kinase Suppressor of Ras 1 (KSR1)-Mediated Extracellular Signal-Regulated Kinase 1/2 Activation, H-Ras^V12-Induced Senescence, and Transformation

Kortum

Fernandez

Costanzo-Garvey

et al. 2014

Molecular and Cellular Biology

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The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates the activation of the Raf/MEK/extracellular signal-regulated kinase (ERK) signal transduction pathway. KSR1 disruption in mouse embryo fibroblasts (MEFs) abrogates growth factor-induced ERK activation, H-Ras V12 -induced replicative senescence, and H-Ras V12 -induced transformation. Caveolin-1 has been primarily described as a major component of the coating structure of caveolae, which can serve as a lipid binding adaptor protein and coordinates the assembly of Ras, Raf, MEK, and ERK. In this study, we show that KSR1 interacts with caveolin-1 and is responsible for MEK and ERK redistribution to caveolin-1-rich fractions. The interaction between KSR1 and caveolin-1 is essential for optimal activation of ERK as a KSR1 mutant unable to interact with caveolin-1 does not efficiently mediate growth factorinduced ERK activation at the early stages of pathway activation. Furthermore, abolishing the KSR1-caveolin-1 interaction increases growth factor demands to promote H-Ras V12 -induced proliferation and has adverse effects on H-Ras V12 -induced cellular senescence and transformation. These data show that caveolin-1 is necessary for optimal KSR1-dependent ERK activation by growth factors and oncogenic Ras.

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A CC-SAM, for Coiled Coil–Sterile α Motif, Domain Targets the Scaffold KSR-1 to Specific Sites in the Plasma Membrane

Cited by 32 publications

References 46 publications

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Molecular basis of MAP kinase regulation

Caveolin-1 Is Required for Kinase Suppressor of Ras 1 (KSR1)-Mediated Extracellular Signal-Regulated Kinase 1/2 Activation, H-Ras^V12-Induced Senescence, and Transformation

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A CC-SAM, for Coiled Coil–Sterile α Motif, Domain Targets the Scaffold KSR-1 to Specific Sites in the Plasma Membrane

Cited by 32 publications

References 46 publications

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Molecular basis of MAP kinase regulation

Caveolin-1 Is Required for Kinase Suppressor of Ras 1 (KSR1)-Mediated Extracellular Signal-Regulated Kinase 1/2 Activation, H-RasV12-Induced Senescence, and Transformation

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Caveolin-1 Is Required for Kinase Suppressor of Ras 1 (KSR1)-Mediated Extracellular Signal-Regulated Kinase 1/2 Activation, H-Ras^V12-Induced Senescence, and Transformation