, Volume 14, Issue 3, pp 345–354 | Cite as

TM4SF1: a tetraspanin-like protein necessary for nanopodia formation and endothelial cell migration

  • Andrew Zukauskas
  • Anne Merley
  • Dan Li
  • Lay-Hong Ang
  • Tracey E. Sciuto
  • Samantha Salman
  • Ann M. Dvorak
  • Harold F. DvorakEmail author
  • Shou-Ching Shih JaminetEmail author
Original Paper


Transmembrane-4-L-six-family-1 (TM4SF1) is a tetraspanin-like membrane protein that is highly and selectively expressed by cultured endothelial cells (EC) and, in vivo, by EC lining angiogenic tumor blood vessels. TM4SF1 is necessary for the formation of unusually long (up to a 50 μm), thin (~100–300 nm wide), F-actin-poor EC cell projections that we term ‘nanopodia’. Immunostaining of nanopodia at both the light and electron microsopic levels localized TM4SF1 in a regularly spaced, banded pattern, forming TM4FS1-enriched domains. Live cell imaging of GFP-transduced HUVEC demonstrated that EC project nanopodia as they migrate and interact with neighboring cells. When TM4SF1 mRNA levels in EC were increased from the normal ~90 mRNA copies/cell to ~400 copies/cell through adenoviral transduction, EC projected more and longer nanopodia from the entire cell circumference but were unable to polarize or migrate effectively. When fibroblasts, which normally express TM4SF1 at ~5 copies/cell, were transduced to express TM4SF1 at EC-like levels, they formed typical TM4SF1-banded nanopodia, and broadened, EC-like lamellipodia. Mass-spectrometry demonstrated that TM4SF1 interacted with myosin-10 and β-actin, proteins involved in filopodia formation and cell migration. In summary, TM4SF1, like genuine tetraspanins, serves as a molecular organizer that interacts with membrane and cytoskeleton-associated proteins and uniquely initiates the formation of nanopodia and facilitates cell polarization and migration.


TM4SF1 Endothelial cell Nanopodia Myosin-10 β-actin 



We thank Dr. Youichiro Wada for helpful discussions. This work was supported by NIH grant P01 CA92644 and by a contract from the National Foundation for Cancer Research.

Supplementary material

10456_2011_9218_MOESM1_ESM.ppt (557 kb)
Supplementary material 1 (PPT 557 kb)

Supplementary material 2 (MOV 6,894 kb)

Supplementary material 3 (MOV 16,580 kb)


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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Andrew Zukauskas
    • 1
  • Anne Merley
    • 1
  • Dan Li
    • 1
  • Lay-Hong Ang
    • 2
  • Tracey E. Sciuto
    • 1
  • Samantha Salman
    • 1
  • Ann M. Dvorak
    • 1
  • Harold F. Dvorak
    • 1
    Email author
  • Shou-Ching Shih Jaminet
    • 1
    Email author
  1. 1.Center for Vascular Biology Research and Department of PathologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  2. 2.Imaging Core FacilityBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA

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