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The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

PNAS, 19 May 2009
Vol. 106, Issue 20, p. 8221-8226
DOI: 10.1073/pnas.0812879106

The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42

  1. Karthikeyan Mythreyea and
  2. Gerard C. Blobea,b,1
  1. Departments of aMedicine and
  2. bPharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708
  1. Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved March 19, 2009 (received for review December 17, 2008)

Abstract

Loss of expression of the TGF-β superfamily coreceptor, the type III TGF-β receptor (TβRIII or betaglycan), occurs in a broad spectrum of human cancers including breast, lung, ovarian, pancreatic, prostate, and renal cell cancer. TβRIII suppresses cancer progression in vivo, at least in part, by reducing cancer cell motility. However, the mechanism by which TβRIII regulates migration is unknown. Here, we demonstrate an unexpected TGF-β signaling independent role for TβRIII in activating Cdc42, altering the actin cytoskeleton and reducing directional persistence to inhibit random migration of both cancer and normal epithelial cells. Functionally, TβRIII through its interaction with the scaffolding protein β-arrestin2, activates Cdc42 and inhibits migration. These studies identify a TGF-β independent homeostatic function for TβRIII in regulating cell migration.

Footnotes

  • 1To whom correspondence should be addressed. E-mail: blobe001{at}mc.duke.edu
  • Author contributions: K.M. and G.C.B. designed research; K.M. performed research; K.M. and G.C.B. analyzed data; and K.M. and G.C.B. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0812879106/DCSupplemental.

Citation:

K. Mythreye and G. C. Blobe, The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42. PNAS 106, 8221-8226 (2009).

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