Cited by 163Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

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Signaling dynamics of the KSR1 scaffold complex

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McKay, Melissa M., Ritt, Daniel A., Morrison, Deborah K.·2009·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0901590106PMC PMC2708738

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Abstract

Scaffold proteins contribute to the spatiotemporal control of MAPK signaling and KSR1 is an ERK cascade scaffold that localizes to the plasma membrane in response to growth factor treatment. To better understand the molecular mechanisms of KSR1 function, we examined the interaction of KSR1 with each of the ERK cascade components, Raf, MEK, and ERK. Here, we identify a hydrophobic motif within the proline-rich sequence (PRS) of MEK1 and MEK2 that is required for constitutive binding to KSR1 and find that MEK binding and residues in the KSR1 CA1 region enable KSR1 to form a ternary complex with B-Raf and MEK following growth factor treatment that enhances MEK activation. We also find that docking of active ERK to the KSR1 scaffold allows ERK to phosphorylate KSR1 and B-Raf on feedback S/TP sites. Strikingly, feedback phosphorylation of KSR1 and B-Raf promote their dissociation and result in the release of KSR1 from the plasma membrane. Together, these findings provide unique insight into the signaling dynamics of the KSR1 scaffold and reveal that through regulated interactions with Raf and ERK, KSR1 acts to both potentiate and attenuate ERK cascade activation, thus regulating the intensity and duration of ERK cascade signaling emanating from the plasma membrane during growth factor signaling.

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Authors: McKay, M. M., Ritt, D. A., & Morrison, D. K.
Affiliations: Frederick National Laboratory for Cancer Research (US)
Yale University (US)
Corresponding author: Morrison, Deborah K.
ORCID: Morrison, Deborah K.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2009-07-07
Volume: 106
Issue: 27
Pages: 11022-11027
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0901590106
PMC: PMC2708738
OpenAlex: W1979514203
Cited by: 163
References: 35
Citations by year: 2026: 2 · 2025: 4 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 12 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 9 · 2016: 14 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 23
FWCI: 7.12
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (ZIABC011107)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: KSR1, scaffold proteins, MAPK signaling, MEK1, MEK2, BRAF, MAPK/ERK pathway, proline-rich sequences, hydrophobic motif, ternary complex, plasma membrane localization, growth factor signaling
MeSH terms: Amino Acid Sequence, Animals, Cell Line, Enzyme Activation, Humans, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Kinases, Signal Transduction, Amino Acid Motifs, Mitogen-Activated Protein Kinase Kinases, Feedback, Physiological, Multiprotein Complexes, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mice, Proline-Rich Protein Domains

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Signaling dynamics of the KSR1 scaffold complex

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