Ras‐Sensitive IMP Modulation of the Raf/MEK/ERK Cascade Through KSR1

Matheny, Sharon A.; White, Michael A.

doi:10.1016/s0076-6879(05)07020-5

Cited by 15 publications

(11 citation statements)

References 22 publications

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“…In addition to their ability to accelerate the kinetics of signaling by different MAPK modules, they are also involved in downregulating the activities of MAPKs in a context specific manner employing different mechanisms (Lu et al, 2002;Willoughby et al, 2003;Witowsky and Johnson, 2003;Matheny and White, 2005;Willoughby and Collins, 2005;Xia et al, 2006). Thus, using both positive and negative signaling inputs, scaffold proteins precisely regulate the signaling outputs from their cognate MAPK-signaling modules.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have unraveled the sequence of events by which the scaffolding function of KSR1 is finely regulated (Xing et al, 1997;Cacace et al, 1999;Muller et al, 2001;Ory et al, 2003;Ory and Morrison, 2004). In quiescent cells, KSR1 interacts Scaffold proteins of MAP-kinase modules DN Dhanasekaran et al constitutively with MEK1/2 and the core domain of PP2A (Ory et al, 2003), and the KSR1-MEK-PP2A complex is retained in the cytosol through its interactions with 14-3-3 and the Ras-sensitive E3-ubiquitin ligase impedes mitogenic signal propagation (IMP) (Raabe and Rapp, 2003;Matheny et al, 2004;Ory and Morrison, 2004;Kolch, 2005;Matheny and White, 2005). Growth factor stimulation leads to the activation of Ras, which stimulates the degradation of IMP thereby relieving its hold on KSR1.…”

Section: Scaffold Proteins In Mammalian Mapk Signaling Modulesmentioning

confidence: 99%

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Scaffold proteins of MAP-kinase modules

et al. 2007

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Mitogen-activated protein kinases (MAPKs) regulate critical signaling pathways involved in cell proliferation, differentiation and apoptosis. Recent studies have shown that a novel class of scaffold proteins mediates the structural and functional organization of the three-tier MAPK module. By linking the MAP3K, MAP2K and MAPK into a multienzyme complex, these MAPKspecific scaffold proteins provide an insulated physical conduit through which signals from the respective MAPK can be transmitted to the appropriate spatiotemporal cellular loci. Scaffold proteins play a determinant role in modulating the signaling strength of their cognate MAPK module by regulating the signal amplitude and duration. The scaffold proteins themselves are finely regulated resulting in dynamic intra-and inter-molecular interactions that can modulate the signaling outputs of MAPK modules. This review focuses on defining the diverse mechanisms by which these scaffold proteins interact with their respective MAPK modules and the role of such interactions in the spatiotemporal organization as well as context-specific signaling of the different MAPK modules.

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Section: Discussionmentioning

confidence: 99%

Section: Scaffold Proteins In Mammalian Mapk Signaling Modulesmentioning

confidence: 99%

Scaffold proteins of MAP-kinase modules

et al. 2007

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“…KSR1 binds to protein phosphatase 2A (17,32) and casein kinase 2 (35), positive regulators of Raf activity (17,32,35). KSR1 is also regulated by a positive feed-forward loop from Ras through IMP (28). Thus, KSR1 coordinates multiple MAPK positive regulatory loops, placing KSR1 in a prime position to regulate MAPK system sensitivity, output, or both.…”

mentioning

confidence: 99%

KSR1 Modulates the Sensitivity of Mitogen-Activated Protein Kinase Pathway Activation in T Cells without Altering Fundamental System Outputs

Lin

Harding

Giurisato

et al. 2009

Molecular and Cellular Biology

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Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that regulate cell fate decisions. They generate a wide range of signal outputs, including graded and digital responses. In T cells, MAPK activation is digital in response to T-cell-receptor stimulation; however, whether other receptors on T cells that lead to MAPK activation are graded or digital is unknown. Here we evaluate MAPK activation in T cells at the single-cell level. We show that T cells responded digitally to stimulation with superantigen-loaded antigen-presenting cells, whereas they responded in a graded manner to the chemokine SDF-1, demonstrating that the system output of the MAPK module is highly plastic and determined by components upstream of the MAPK module. These findings also confirm that different MAPK system outputs are used by T cells to control discrete biological functions. Scaffold proteins are essential for proper MAPK signaling and function as they physically assemble multiple components and regulators of MAPK cascades. We found that the scaffold protein KSR1 regulated the threshold required for MAPK activation in T cells without affecting the nature of the response. We conclude that KSR1 plays a central role in determining the sensitivity of T-cell responses and is thus well positioned as a key control point.

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“…While the C-terminus of Brap showed a strong interaction with LIS1, neither the N-terminus of Brap nor a larger construct that includes the domain involved in ubiquitin E3 activity showed detectable LIS1 binding (Figure 5C). Since the previously reported minimal Ras binding domain (RBD) largely overlaps with the UBP-ZnF but not in the C-terminus (Matheny et al, 2004; Matheny and White, 2006), our data indicate that Brap interacts with LIS1 directly with its C-terminus coiled-coil. Such interaction should not directly block the function of Brap as an E3 ubiquitin-protein ligase, protease, or a Ras effector in MAPK signaling regulation.…”

Section: Resultsmentioning

confidence: 52%

Spatially Dependent Dynamic MAPK Modulation by the Nde1-Lis1-Brap Complex Patterns Mammalian CNS

et al. 2013

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Summary Regulating cell proliferation and differentiation in CNS development requires both extraordinary complexity and precision. Neural progenitors receive graded overlapping signals from midline signaling centers, yet each makes a unique cell fate decision in a spatiotemporally restricted pattern. The Nde1-Lis1 complex regulates individualized cell fate decisions based on the geographical location with respect to the midline. While cells distant from the midline fail to self-renew in the Nde1-Lis1 double mutant CNS, cells embedded in the signaling centers showed marked over-proliferation. A direct interaction between Lis1 and Brap, a MAPK signaling threshold modulator, mediates this differential response to mitogenic signal gradients. Nde1-Lis1 deficiency resulted in a spatially-dependent alteration of MAPK scaffold Ksr and hyper-activation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions. These results suggest that a molecular complex composed of Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially-dependent fashion.

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Ras‐Sensitive IMP Modulation of the Raf/MEK/ERK Cascade Through KSR1

Cited by 15 publications

References 22 publications

Scaffold proteins of MAP-kinase modules

Scaffold proteins of MAP-kinase modules

KSR1 Modulates the Sensitivity of Mitogen-Activated Protein Kinase Pathway Activation in T Cells without Altering Fundamental System Outputs

Spatially Dependent Dynamic MAPK Modulation by the Nde1-Lis1-Brap Complex Patterns Mammalian CNS

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