APPL Proteins Link Rab5 to Nuclear Signal Transduction via an Endosomal Compartment

Signals generated in response to extracellular stimuli at the plasma membrane are transmitted through cytoplasmic transduction cascades to the nucleus. We report the identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogen...

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Bibliographic Details
Published in:Cell 2004-02, Vol.116 (3), p.445-456
Main Authors: Miaczynska, Marta, Christoforidis, Savvas, Giner, Angelika, Shevchenko, Anna, Uttenweiler-Joseph, Sandrine, Habermann, Bianca, Wilm, Matthias, Parton, Robert G, Zerial, Marino
Format: Article
Language:English
Subjects:
Binding Sites - genetics
Biochemistry, Molecular Biology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Compartmentation - genetics
Cell Division - genetics
Cell Membrane - metabolism
Cell Membrane - ultrastructure
Cell Nucleus - metabolism
Cell Nucleus - ultrastructure
Endocytosis - physiology
Endosomes - metabolism
Endosomes - ultrastructure
Guanosine Triphosphate - metabolism
HeLa Cells
Histone Deacetylases - genetics
Humans
Life Sciences
Mi-2 Nucleosome Remodeling and Deacetylase Complex
Microscopy, Electron
Protein Binding - genetics
Protein Transport - genetics
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
rab5 GTP-Binding Proteins - genetics
rab5 GTP-Binding Proteins - metabolism
Signal Transduction - genetics
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Summary:Signals generated in response to extracellular stimuli at the plasma membrane are transmitted through cytoplasmic transduction cascades to the nucleus. We report the identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogenesis. This pathway operates via APPL1 and APPL2, two Rab5 effectors, which reside on a subpopulation of endosomes. In response to extracellular stimuli such as EGF and oxidative stress, APPL1 translocates from the membranes to the nucleus where it interacts with the nucleosome remodeling and histone deacetylase multiprotein complex NuRD/MeCP1, an established regulator of chromatin structure and gene expression. Both APPL1 and APPL2 are essential for cell proliferation and their function requires Rab5 binding. Our findings identify an endosomal compartment bearing Rab5 and APPL proteins as an intermediate in signaling between the plasma membrane and the nucleus.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(04)00117-5