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 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.
Miaczynska
Marta
M
Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Christoforidis
Savvas
S
Giner
Angelika
A
Shevchenko
Anna
A
Uttenweiler-Joseph
Sandrine
S
Habermann
Bianca
B
Wilm
Matthias
M
Parton
Robert G
RG
Zerial
Marino
M
D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D008854:Microscopy, Electron; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport / Q000235:genetics; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000235:genetics; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; D006160:Guanosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D020696:rab5 GTP-Binding Proteins