Signalling from Endosomes and Exosomes


Cellular signalling is a dynamic process that underlies all aspects of organismal development, function and disease. While signal transduction at the plasma membrane has received a great deal of attention, we now appreciate that activated receptors reside at the plasma membrane for only a small fraction of their life‐time. Upon activation by ligand, these receptors are often internalised and sorted into different membrane‐bound compartments that allows for enhanced, modified or quenched signalling. Herein we focus on post‐endocytic signalling cargo as it traverses compartments including early endosomes, multivesicular bodies, lysosomes, synaptic vesicles or exosomes.

Key Concepts

  • Much of cellular signal transduction emanates from endosomal membranes
  • Sorting, trafficking and maturation in endosomes are major regulators of signal transduction.
  • Exosome biogenesis and secretion is an emergent property of cell–cell communication and a target for dysregulation in disease

Keywords: endosomes; exosomes; early endosomes; multivesicular bodies; phagosomes; synaptic vesicle; signal transduction; cell–cell communication

Figure 1. The Endosomal Life Cycle. EGFR bound to its ligand is endocytosed through either clathrin‐mediated or ‐independent mechanisms into clathrin‐coated vesicles. These vesicles fuse with the early endosome (EE) in a Rab5‐dependent manner. Rab4/11‐rich microdomains in the EE recycle back to the plasma membrane, whereas Rab5‐rich domains mature into multivesicular endosomes (MVE) with Rab7 present. MVEs either fuse with the plasma membrane to secrete exosomes or mature into the lysosome. The lysosome is the final destination of materials signals from the autophagosome endosomes to be quenched. Through each step of maturation, v‐ATPases decrease pH.
Figure 2. The Synaptic Vesicle Cycle. Membrane‐bound vesicles containing neurotransmitters travel to the axon terminal. These vesicles are primed for docking by MUNC family proteins. The vesicles dock to the terminal membrane. t‐SNARE and v‐SNARE proteins interact, fusing the two membranes and resulting in the release of neurotransmitters into the synapse.


Ailawadi S, Wang X, Gu H et al. (2015) Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochimica et Biophysica Acta 1852 (1): 1–11.

Bache KG, Slagsvold T and Stenmark H (2004) Defective downregulation of receptor tyrosine kinases in cancer. The EMBO Journal 23 (14): 2707–2712.

Bang C, Batkai S, Dangwal S, et al. (2014) Cardiac fibroblast‐derived microRNA passenger strand‐enriched exosomes mediate cardiomyocyte hypertrophy. Journal of Clinical Investigation 124 (5): 2136–2146.

Bhuin T and Kumar J (2014) Rab proteins: the key regulators of intracellular vesicle transport. Experimental Cell Research 8: 1–19.

Bitsikas V, Corrêa IR and Nichols BJ (2014) Clathrin‐independent pathways do not contribute significantly to endocytic flux. eLife 3: 1–26.

Cataldo A, Barnett J and Pieroni C (1997) Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased. The Journal of Neuroscience 17 (16): 6142–6151.

Cataldo A, Peterhoff C, Troncoso J, et al. (2000) Endocytic pathway abnormalities precede amyloid. American Journal of Pathology 157 (1): 277–286.

Citri A, Alroy I, Lavi S, et al. (2002) Drug‐induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO Journal 21 (10): 2407–2417.

Clayton A, Mitchell JP, Court J, Mason MD and Tabi Z (2007) Human tumor‐derived exosomes selectively impair lymphocyte responses to interleukin‐2. Cancer Research 67 (15): 7458–7466.

Cogli L, Piro F and Bucci C (2009) Rab7 and the CMT2B disease. Biochemical Society Transactions 37 (5): 1027–1031.

Corrado C, Raimondo S, Chiesi A, et al. (2013) Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. International Journal of Molecular Sciences 14 (3): 5338–5366.

Deák F, Xu Y, Chang WP, et al. (2009) Munc18‐1 binding to the neuronal SNARE complex controls synaptic vesicle priming. The Journal of Cell Biology 184 (5): 751–764.

Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W and Geuze HJ (2000) Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. Journal of Cell Science 113 (19): 3365–3374.

Haglund K and Dikic I (2012) The role of ubiquitylation in receptor endocytosis and endosomal sorting. Journal of Cell Science 125 (2): 265–275.

Hata Y, Claughter CA and Sudhof TC (1993) Synaptic vesicle fusion complex contains Unc‐18 homologue bound to syntaxin. Nature 363 (6453): 347–351.

Hinshaw JE (2000) Dynamin and its role in membrane fission. Annual Review of Cell and Developmental Biology 16: 483–519.

Jovic M, Sharma M, Rahajeng J and Caplan S (2010) The early endosome: a busy sorting station for proteins at the crossroads. Histology Histopathology 25 (1): 99–112.

Lee S, Chin L and Li L (2012) Charcot‐Marie‐Tooth disease‐linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking. Journal of Cell Biology 199 (5): 799–816.

Lin RC and Scheller RH (1997) Structural organization of the synaptic exocytosis core complex. Neuron 19 (5): 1087–1094.

Ma C, Li W, Xu Y and Rizo J (2011) Munc13 mediates the transition from the closed syntaxin‐Munc18 complex to the SNARE complex. Changes 18 (5): 542–549.

Maxfield F and McGraw T (2004) Endocytic recycling. Nature Reviews 5: 121–132.

McCready J, Sims JD, Chan D and Jay DG (2010) Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer 10: 294.

Medina DL, Di Paola S, Peluso I, et al. (2015) Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nature Cell Biology 17 (3): 288–299.

Melo SA, Sugimoto H, Connell JTO, et al. (2014) Article cancer exosomes perform cell‐independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26 (5): 707–721.

Miaczynska M, Pelkmans L and Zerial M (2004) Not just a sink: endosomes in control of signal transduction. Current Opinion in Cell Biology 16 (4): 400–406.

Mizushima N (2007) Autophagy: process and function. Genes and Development 21 (22): 2861–2873.

Nixon RA, Yang DS and Lee JH (2008) Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4 (5): 590–599.

Pahl A, Severin F, Lommer B, Shevchenko A and Zerial M (2006) Huntingtin–HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up‐regulated in Huntington's disease. Max Planck Institute of Molecular Cell Biology and Genetics 172 (4): 605–618.

Pálfy M, Reményi A and Korcsmáros T (2012) Endosomal crosstalk: meeting points for signaling pathways. Trends in Cell Biology 22 (9): 447–456.

Panic B, Whyte JR, Munro S, et al. (2011) mTORC1 senses lysosomal amino acids. Science 334 (6056): 678–683.

Paolo P, Fiore D and Zastrow MV (2014) Endocytosis, signaling, and beyond. Cold Spring Harbor Perspectives in Biology 6 (8).

Pearse B, Smith C and Owen D (2000) Clathrin coat construction in endocytosis. Current Opinions in Structural Biology 10: 220–228.

Rabinowits G, Gerçel‐Taylor C, Day JM, Taylor DD and Kloecker GH (2009) Exosomal microRNA: a diagnostic marker for lung cancer. Clinical Lung Cancer 10 (1): 42–46.

Rajendran L, Honsho MM, Zahn TR, et al. (2006) Alzheimer's disease beta‐amyloid peptides are released in association with exosomes. Proceedings of the National Academy of Sciences United States of America 103 (50): 11172–11177.

Sheldon H, Heikamp E, Turley H, et al. (2010) New mechanism for Notch signaling to endothelium at a distance by delta‐like 4 incorporation into exosomes. Blood 116 (13): 2385–2394.

Skog J, Würdinger T, van Rijn S, et al. (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biology 10 (12): 1470–1476.

Skokos D, Botros HG, Demeure C, et al. (2003) Mast cell‐derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. Journal of Immunology (Baltimore, Md.: 1950) 170 (6): 3037–3045.

Sørensen JB (2005) SNARE complexes prepare for membrane fusion. Trends in Neurosciences 28 (9): 453–455.

Stenmark H (2009) Rab GTPase as coordinators of vesicle traffic. Nature Reviews 10: 513–525.

Sudhof T (2004) The synaptic vesicle cycle. Annual Review of Neuroscience 27: 509–547.

Suo D, Park J, Harrington A, et al. (2014) Coronin‐1 is a neurotrophin endosomal effector required for developmental competition for survival. Nature Neuroscience 17 (1): 36–45.

Tate B and Mathews P (2006) Targeting the role of the endosome in the pathophysiology of Alzeheimer's disease: a strategy for treatment. Science of Aging Knowledge Environment 10: re2.

Taelman V, Dobrowolski R, Plouhinec JL, et al. (2010) Wnt Signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell 143: 1136–1148.

Urbanelli L, Magini A, Buratta S, et al. (2013) Signaling pathways in exosomes biogenesis, secretion and fate. Genes 4 (2): 152–170.

Further Reading

Azmi A, Bao B and Sarkar F (2014) Exosomes in cancer development, metastasis and drug resistance: a comprehensive review. Cancer Metastasis Reviews 32 (3–4): 623–642.

Raposo G and Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. Journal of Cell Biology 200 (4): 373–383.

Sadowski L, Pilecka I and Miaczynska M (2009) Signaling from endosomes: location makes a difference. Experimental Cell Research 315: 1601–1609.

Scott C, Vacca F and Gruenberg J (2014) Endosome maturation, transport and functions. Seminars in Cell & Developmental Biology 31: 2–10.

Théry C, Zitvogel L and Amigorena S (2002) Exosomes: composition, biogenesis and function. Nature Reviews. Immunology 2 (8): 569–579.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Huckaby, Adam, Dombrovski, Mark, Maher, Erin, Naimi, Waheeda, Perez, Matthew, Skyberg, Rolf, Smolko, Christian, Barford, Kelly, Winckler, Bettina, and Deppmann, Christopher(Nov 2015) Signalling from Endosomes and Exosomes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026278]