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The ESCRT machinery regulates Akt signaling mediated by the G protein‐coupled receptor CXCR4
Author(s) -
Verma Rita,
Marchese Adriano
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.556.6
Subject(s) - escrt , protein kinase b , endosome , microbiology and biotechnology , phosphorylation , internalization , signal transduction , biology , chemistry , biochemistry , receptor , intracellular
The chemokine receptor CXCR4/stromal cell‐derived factor (SDF)‐1 alpha signaling axis is important in health and disease. Dysregulated CXCR4 signaling has been linked to cardiovascular disease, WHIM syndrome and cancer. However, despite the role of aberrant CXCR4 signaling in disease, the molecular mechanisms that govern CXCR4 signaling are poorly understood. The objective of this study is to elucidate the molecular mechanisms that govern CXCR4 signaling. Activated CXCR4 is rapidly ubiquitinated and sorted for lysosomal degradation via the endosomal sorting complex required for transport (ESCRT) machinery. The ESCRT machinery (ESCRT‐0, I, II and III) act in a coordinated manner to target ubiquitinated membrane proteins into intraluminal vesicles of multivesicular bodies for subsequent lysosomal degradation. While the ESCRT machinery mediates downregulation of CXCR4, our data indicate that it also has a novel positive role in CXCR4 signaling. Here, we provide evidence that the ESCRT machinery mediates CXCR4‐induced activation of Akt. Our data indicate that depletion of ESCRT‐0, I and II by siRNA inhibits CXCR4‐induced phosphorylation of Akt on serine 473, which corresponds to a decrease in Akt activity as phosphorylation of Tsc2, an Akt substrate, is also reduced. We show that Tsg101 (an ESCRT‐I subunit) interacts directly with Akt and under basal conditions Tsg101 and Akt are constitutively associated, as assessed by co‐immunoprecipitation; CXCR4 activation disrupts this interaction. Our data also reveal that CXCR4 internalization is required for Akt activation. Therefore CXCR4‐induced Akt activation is mediated by CXCR4 internalization onto endosomes and by the ESCRT machinery. This work was supported by grants from the AHA and the NIGMS.