Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade
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Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-terminal region of both proteins binds to the scaffold protein IB2/JIP2. IB2/JIP2 is a scaffold for the p38 mitogen-activated protein (MAP) kinase cascade because it binds to the Rac target MLK3, the MAP kinase kinase MKK3, and the p38 MAP kinase. Expression of IB2/JIP2 in cells potentiates the ability of Tiam1 or Ras-GRF1 to activate the p38 MAP kinase cascade but not the Jnk MAP kinase cascade. In addition, Tiam1 or Ras-GRF1 binding to IB2/JIP2 increases the association of the components of the p38 MAP kinase signaling cassette with IB2/JIP2 in cells and activates scaffold-associated p38. These findings imply that Tiam1 and Ras-GRF1 can contribute to Rac signaling specificity by their ability to form a complex with a scaffold that binds components of one of the many known Rac effector pathways.
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JIP1/2 interact with Tiam1.
“It has previously been reported that c-jun-terminal kinase interacting proteins 1/2 (JIP1/2) interact with ApoER2 (Stockinger et al., 2000) as well as Tiam1 (Buchsbaum et al., 2002), the major Rac guanine nucleotide exchange factor that couples the NMDAR to Rac1 (Tolias et al., 2005).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Buchsbaum et al., 2002
Postsynaptic JIP and Tiam1 could be involved in mediating the effects of IDOL-ApoER2 axis on Rac1 activity.
“Our data suggest that postsynaptic JIP (Stockinger et al., 2000; Verhey et al., 2001) and Tiam1 (Buchsbaum et al., 2002) could be involved in mediating the effects of IDOL-ApoER2 axis on Rac1 activity.”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Buchsbaum et al., 2002
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“One documented IB1/JIP1 and IB2/JIP2 binding partner is ApoER2, a receptor for neuronal Reelin that plays a key role in neuronal development (38).”
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- Authors
- Buchsbaum, R. J., Connolly, B. A., & Feig, L. A.
- Affiliations
- Tufts University (US)
- Corresponding author
- Feig, Larry A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-06-01
- Volume
- 22
- Issue
- 12
- Pages
- 4073-4085
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC133864
- OpenAlex
- W2159303181
- Cited by
- 198
- References
- 3
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 8 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 9 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 11
- FWCI
- 5.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, San Francisco
- National Cancer Institute
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- Tiam1, guanine nucleotide exchange factor, Rac GTPase, scaffold proteins, MAPK signaling, MLK3, MKK3, JNK MAP kinase, pleckstrin homology domain, coiled-coil domain, signaling specificity, protein complex formation
- MeSH terms
- T-Lymphoma Invasion and Metastasis-inducing Protein 1, Mitogen-Activated Protein Kinase Kinase Kinase 11, Amino Acid Sequence, Animals, Binding Sites, Carrier Proteins, DNA-Binding Proteins, Humans, Molecular Sequence Data, Neoplasm Proteins, Plant Proteins, Proteins, Sequence Homology, Amino Acid, COS Cells, Guanine Nucleotide Exchange Factors, ras-GRF1, Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Adaptor Proteins, Signal Transducing, Rats
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