Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors
Open accessAbstract
The involvement of Ral and its downstream molecules in receptor-mediated endocytosis was examined. Expression of either RalG23V or RalS28N, which are known to be constitutively active and dominantnegative forms, respectively, in A431 cells blocked internalization of epidermal growth factor (EGF). Stable expression of RalG23V or RalS28N in CHO-IR cells also inhibited internalization of insulin. Internalization of EGF and insulin was not affected by full-length RalBP1 which is an effector protein of Ral, but was inhibited by its C-terminal region which binds directly to Ral and POB1. POB1 is a binding protein of RalBP1 and has the Eps15 homology (EH) domain. Deletion mutants of POB1 inhibited internalization of EGF and insulin. However, internalization of transferrin was unaffected by Ral, RalBP1, POB1 and their mutants. Epsin and Eps15 have been reported to be involved in the regulation of endocytosis of the receptors for EGF and transferrin. The EH domain of POB1 bound directly to Epsin and Eps15. Taken together with the observation that EGF and insulin activate Ral, these results suggest that Ral, RalBP1 and POB1 transmit the signal from the receptors to Epsin and Eps15, thereby regulating ligand-dependent receptor-mediated endocytosis.
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Previous studies of Reps1 and Ralbp1 in endocytosis were based on overexpression of dominant-negative mutants in WT cells, precluding direct assessment of their roles in CME.
“Previous studies of Reps1 and Ralbp1 in endocytosis, however, were based on overexpression of dominant-negative mutants in WT cells, precluding direct assessment of their roles in CME (63, 64).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [64]
The Results and Discussion (page unavailable) describe expressing RalBP1 deletion mutants in A431 and CHO-IR cells and report that mutants, but not full-length proteins, inhibited receptor internalization. The paper studies POB1, not Reps1; the Introduction identifies Reps1 only as a POB1-related protein. It does not directly assess Reps1’s role in clathrin-mediated endocytosis. (LLM, conf=0.87)
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Cites
Chen, H., Slepnev, V. I., Di Fiore, P. P., & De Camilli, P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.6.3257 · Cited by 138 · see citing works
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- McGraw,T.E. and Maxfield,F.R. (1990) Human transferrin receptor internalization is partially dependent upon an aromatic amino acid on the cytoplasmic domain. Cell Regul., 1, 369-377.
- Morinaka,K., Koyama,S., Nakashima,S., Hinoi,T., Okawa,K., Iwamatsu,A. and Kikuchi,A. (1999) Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis. Oncogene, in press.
- Wong,W.T., Schumacher,C., Salcini,A.E., Romano,A., Castagnino,P., Pelicci,P.G. and Di Fiore,P.P. (1995) A protein-binding domain, EH, identified in the receptor tyrosine kinase substrate Eps15 and conserved in evolution. Proc. Natl Acad. Sci. USA, 92, 9530-9534.
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Ral signaling pathway in health and cancer
Moghadam, A. R., Patrad, E., Tafsiri, E., Peng, W., Fangman, B., Pluard, T. J., Accurso, A., Salacz, M., Shah, K., Ricke, B., et al. (2017) · Cancer Medicine · doi:10.1002/cam4.1105 · Cited by 58 · see citing works
Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module
Wang, S., Chen, X., Crisman, L., Dou, X., Winborn, C. S., Wan, C., Puscher, H., Yin, Q., Kennedy, M. J., & Shen, J. (2023) · Science Advances · doi:10.1126/sciadv.ade2540 · Cited by 14 · see citing works
- Authors
- Nakashima, S., Morinaka, K., Koyama, S., Ikeda, M., Kishida, M., Okawa, K., Iwamatsu, A., Kishida, S., & Kikuchi, A.
- Affiliations
- Hiroshima University (JP)
- Kirin (Japan) (JP)
- Corresponding author
- Kikuchi, Akira
- Venue
- The EMBO Journal
- Published
- 1999-07-01
- Volume
- 18
- Issue
- 13
- Pages
- 3629-3642
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1171441
- OpenAlex
- W2109110743
- Cited by
- 231
- References
- 1
- Citations by year
- 2025: 3 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 9 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 9
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Hiroshima University Institutional Repository (submittedVersion, other-oa)
- Funders
- Naito Foundation
- Kato Memorial Bioscience Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Ral GTPase, receptor-mediated endocytosis, insulin receptor internalization, RALBP1, Eps15 homology domain, epsin, Eps15, EGF signaling, transferrin internalization
- MeSH terms
- Amino Acid Sequence, Animals, Calcium-Binding Proteins, Carrier Proteins, Cattle, Cell Line, Endocytosis, Epidermal Growth Factor, Fungal Proteins, Cricetinae, Humans, Insulin, Molecular Sequence Data, Mutation, Neuropeptides, Phosphoproteins, Protein Binding, Receptor, Insulin, Recombinant Fusion Proteins, Transferrin, Signal Transduction, CHO Cells, GTP-Binding Proteins, GTPase-Activating Proteins, ral GTP-Binding Proteins, Vesicular Transport Proteins, Adaptor Proteins, Vesicular Transport, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, ErbB Receptors
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