CIN85 Associates with Multiple Effectors Controlling Intracellular Trafficking of Epidermal Growth Factor Receptors
Open accessAbstract
CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. CIN85 src homology 3 domains specifically bind to a proline-arginine (PxxxPR) motif in Cbl, and this association seems to be important for EGF receptor endocytosis. Here, we report identification of novel CIN85 effectors, all containing one or more PxxxPR motifs, that are indispensable for their mutual interactions. These effectors include phosphatidyl-inositol phosphatases SHIP-1 and synaptojanin 2B1, Arf GTPase-activating proteins ASAP1 and ARAP3, adaptor proteins Hip1R and STAP1, and a Rho exchange factor, p115Rho GEF. Acting as a molecular scaffold, CIN85 clusters its effectors and recruits them to high-molecular-weight complexes in cytosolic extracts of cells. Further characterization of CIN85 binding to ASAP1 revealed that formation of the complex is independent on cell stimulation. Overexpression of ASAP1 increased EGF receptor recycling, whereas ASAP1 containing mutated PxxxPR motif failed to promote this event. We propose that CIN85 functions as a scaffold molecule that binds to numerous endocytic accessory proteins, thus controlling distinct steps in trafficking of EGF receptors along the endocytic and recycling pathways.
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We detected several SHIP1 binding partners previously identified in other myeloid cells, such as SH3KBP1, GRB2, SHC1, DOK2, ARAP1, CD2AP.
“We detected several SHIP1 binding partners previously identified in other myeloid cells, such as SH3KBP117, GRB218, SHC118, DOK218,19, ARAP120 and CD2AP21 (Figure 1D).”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [18]
SHIP1 regulates these signaling events by binding to important adaptor proteins in the cytoplasm, such as SHC1, DOK2, GRB2 and others in lymphoid and hematopoietic cells.
“SHIP1 regulates these signaling events by binding to important adaptor proteins in the cytoplasm, such as SHC1, DOK2, GRB2 and others in lymphoid and hematopoietic cells18,19.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [18]
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References 66 · Cited by 128
- Authors
- Kowanetz, K., Husnjak, K., Höller, D., Kowanetz, M., Soubeyran, P., Hirsch, D., Schmidt, M. H. H., Pavelic, K., De Camilli, P., Randazzo, P. A., & Dikic, I.
- Affiliations
- Goethe University Frankfurt (DE)
- Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt, Germany
- Ludwig Cancer Research (SE)
- National Cancer Institute (US)
- Rudjer Boskovic Institute, Division of Molecular Medicine, 10 000 Zagreb, Croatia
- Department of Cell Biology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510
- Venue
- Molecular Biology of the Cell
- Published
- 2004-07
- Volume
- 15
- Issue
- 7
- Pages
- 3155-3166
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC452573
- OpenAlex
- W2168709504
- Cited by
- 128
- References
- 66
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 5
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Princeton University
- Boehringer Ingelheim Stiftung
- 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
- CIN85, epidermal growth factor receptor, receptor internalization, receptor recycling, intracellular trafficking, CBL, adaptor proteins, ASAP1, HIP1R, STAP1, SHIP1, Arf GTPase-activating protein, molecular scaffolds, endocytic pathway
- MeSH terms
- Binding Sites, Cell Line, Humans, Receptors, Transferrin, Transferrin, Protein Structure, Tertiary, GTPase-Activating Proteins, Amino Acid Motifs, Protein Transport, Intracellular Space, Adaptor Proteins, Signal Transducing, ErbB Receptors
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