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Mol Cell Biol. 2017 Sep 12;37(19). pii: e00171-17. doi: 10.1128/MCB.00171-17. Print 2017 Oct 1.

PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion.

Author information

1
Department of Dermatology and Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, California, USA.
2
Department of Pediatrics, Children's Center for Cancer and Blood Diseases and Saban Research Institute, Children's Hospital Los Angeles, University of Southern California Keck Medical Center, Los Angeles, California, USA.
3
Department of Molecular Microbiology and Immunology, University of Southern California Keck Medical Center, Los Angeles, California, USA.
4
Department of Dermatology and Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, California, USA wli@usc.edu.

Abstract

Secreted exosomes carrying lipids, proteins, and nucleic acids conduct cell-cell communications within the microenvironment of both physiological and pathological conditions. Exosome secretion is triggered by extracellular or intracellular stress signals. Little is known, however, about the signal transduction between stress cues and exosome secretion. To identify the linker protein, we took advantage of a unique finding in human keratinocytes. In these cells, although transforming growth factor alpha (TGF-α) and epidermal growth factor (EGF) share the same EGF receptor and previously indistinguishable intracellular signaling networks, only TGF-α stimulation causes exosome-mediated secretion. However, deduction of EGF-activated pathways from TGFα-activated pathways in the same cells allowed us to identify the proline-rich Akt substrate of 40 kDa (PRAS40) as the unique downstream effector of TGF-α but not EGF signaling via threonine 308-phosphorylated Akt. PRAS40 knockdown (KD) or PRAS40 dominant-negative (DN) mutant overexpression blocks not only TGF-α- but also hypoxia- and H2O2-induced exosome secretion in a variety of normal and tumor cells. Site-directed mutagenesis and gene rescue studies show that Akt-mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion without affecting the endoplasmic reticulum/Golgi pathway. Identification of PRAS40 as a linker protein paves the way for understanding how stress regulates exosome secretion under pathophysiological conditions.

KEYWORDS:

Akt; HIF-1; HSP; exosome; growth factor; signal transduction; stress

PMID:
28674187
PMCID:
PMC5599722
DOI:
10.1128/MCB.00171-17
[Indexed for MEDLINE]
Free PMC Article

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