Cell-penetrating peptide exploited syndecans

Biochim Biophys Acta. 2010 Dec;1798(12):2258-65. doi: 10.1016/j.bbamem.2010.01.022. Epub 2010 Feb 2.


Cell-penetrating peptides (CPPs) are short peptides capable of translocating across the plasma membrane of live cells and transporting conjugated compounds intracellularly. Fifteen years after discovering the first model cationic CPPs, penetratin and TAT, CPP internalization is still challenging many questions. Particularly it has been unknown whether CPPs enter the cells with or without mediation of a specific surface receptor. Here we report that syndecan-4, the universally expressed isoform of the syndecan family of transmembrane proteoglycans, binds and mediates transport of the three most frequently utilized cationic CPPs (penetratin, octaarginine and TAT) into the cells. Quantitative uptake studies and mutational analyses demonstrate that attachment of the cationic CPPs is mediated by specific interactions between the heparan sulfate chains of syndecan-4 and the CPPs. Protein kinase C alpha is also heavily involved in the uptake mechanism. The collected data give the first direct evidence on the receptor-mediated uptake of cationic CPPs and may replace the long-thought, but already contradicted membrane penetration hypothesis. Thus our study might give an answer for a decade long debate and foster the development of rationalized, syndecan-4 targeted novel delivery technologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Cell-Penetrating Peptides / chemistry
  • Cell-Penetrating Peptides / pharmacokinetics*
  • Cell-Penetrating Peptides / pharmacology*
  • Drug Delivery Systems / methods*
  • Heparitin Sulfate / genetics
  • Heparitin Sulfate / metabolism
  • Humans
  • K562 Cells
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Syndecan-4 / chemistry
  • Syndecan-4 / metabolism*


  • Cell-Penetrating Peptides
  • Protein Isoforms
  • SDC4 protein, human
  • Syndecan-4
  • Heparitin Sulfate
  • Protein Kinase C-alpha