Philip D. Stahl, Ph.D.

Edward Mallinckrodt Jr Professor Emeritus
Cell Biology and Physiology

General Program

  • 314-362-6913

  • 314-362-1081

  • 314-362-1490

  • 4912 South Building

  • pstahl@wustl.edu

  • Exosomes, endocytosis, hominoid-specific genes

  • Exosomes- biogenesis and secretion. Hominoid-specific genes such as TBC1D3, that regulate growth factor receptor signaling, may help explain human evolution and physiology

Research Abstract:

Exosomes and cell signaling. Our 1983 discovery paper paved the way for the development and growth of a brand new field of biomedical research- exosomes and intercellular communication. The exosome secretion pathway was first characterized and visualized by tagging transferrin, the iron transport protein, with colloidal gold particles in reticulocytes. Transferrin (Tf) avidly binds the transferrin receptor (Tf-R) and tracks the Tf-R as it recycles through the endocytic network. As the reticulocyte matures, a fraction of internalized Tf-R receptors are packaged into multivesicular bodies. Multivesicular bodies were exclusively thought to conduit internalized materials to the lysosomes for degradation. However, in Clifford Harding’s thesis work, multivesicular bodies were shown to fuse with the plasma membrane releasing 50-100 nanometer particles into the extracellular space. The nanoparticles are now called exosomes and their secretion is now referred to as the exosome biogenesis and secretion pathway. More recent work revealed that all cells, plants and animal alike, secrete exosomes that contain signaling proteins and a range of RNA molecules including miRNA. Exosomes transport miRNA and signaling proteins from one cell to another creating a novel, and apparently wide spread, intercellular communications pathway. The exosome secretion pathway is universal-- all cells do it. Below is the diagram of the findings from the original Harding et.al 1983 Journal of Cell Biology paper (left) and a colorful version (right) from a recent review (Stahl and Raposo, see below).

Hominoid specific genes. The human genome contains any number of unique protein encoding genes only found in humans and other hominoids. The numbers could range in the hundreds-new genes can be truncations or mutations of existing genes, result from segmental duplication or as a result of transposon insertion. Hominoid-specific genes and the proteins that they encode are likely to reveal unique cellular and molecular characteristics that are human-only and that function to set us apart from lower organisms. We uncovered a hominoid-specific genes called TBC1D3 that regulates signal transduction via the EGF and other growth factor receptors. Recent work from other groups indicates that selective expression of TBC1D3 in human brain leads to the proliferation of a sub set of cells that enhance neurogenesis.

Selected Publications:

Exosomes and cell signaling
CV Harding , JE Heuser & PD Stahl (1983) Receptor Mediated Endocytosis of Transferrin and Recycling of the Transferrin Receptor in Rat Reticulocytes. Journal of Cell Biology 97, 329.

CV Harding, JE Heuser & PD Stahl (2013) Exosomes: Looking back three decades and into the future. Journal of Cell Biology 200, 367.

PD Stahl PD & G Raposo (2019) Extracellular Vesicles: Exosomes and Microvesicles, Integrators of Homeostasis. Physiology 34:169-177. Doi:1152/physiol.00045.2018.

G Raposo & PD Stahl (2019) Extracellular vesicles: a new communications paradigm? Nature Reviews:Molecular Cell Biology 20, 509.

Hominoid specific genes
PD Stahl PD & MJ Wainszelbaum (2009) Human-specific genes may offer a unique window into human cell signaling. Science Signaling 2(89):pe59. Review. NIHMSID: NIHMS148158.

D Hodzic, C Kong, MJ Wainzelbaum, AJ Charron, X Su & PD Stahl (2006) TBC1D3, a hominoid oncoprotein, is encloded by a cluster of paralogues located on chromosome 17q12. Genomics 88:731-736.

MJ Wainszelbaum, AJ Charron, C Kong, DS Kirkpatrick, P Srikanth, MA Barbieri, SP Gygi & PD Stahl (2008) The hominoid-specific oncogene TBC1D3 activates Ras and modulates EGF receptor signaling and trafficking. J Biol Chem 283(19):13233-13242. PMCID: PMC2442359

MJ Wainszelbaum, J Liu, C Kong, P Srikanth, D Samovski, X Su & PD Stahl (2012) TBC1D3, a hominoid-specific gene, delays IRS-1 degradation and promotes insulin signaling by modulating PP2A activity. PLoS:ONE. 7(2):e31225.

C Kong, D Samovski, P Srikanth, MJ Wainszelbaum, AJ Charron, J Liu, JJ Lange, PI Chen, ZQ Pan, X Su X & PD Stahl (2012) Ubiquitination and degradation of the hominoid-specific oncogene TBC1D3 is mediated by Cul7 E3 ligase. PLoS ONE 7(9):e46485.

C Kong, JJ Lange, D Samovski, X Su, J Liu, S Sundaresan & PD Stahl (2013) Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation. Biochem Biophys Res Commun. 434(2):388-93.

S Qin, RA Dorschner, I Masini, O Lavoie-Gagne, PD Stahl, TW Costantini, A Baird & B Eliceiri (2019) TBC1D3 regulates the payload and biological activity of extracellular vesicles that mediate tissue repair. FASEB J. 33(5):6129-6139. doi: 10.1096/fj.201802388R.

Last Updated: 9/30/2019 10:58:10 AM

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