Published online
doi:10.1083/jcb.200708123
The Journal of Cell Biology, Vol. 180, No. 6, 1245-1260
The Rockefeller University Press, 0021-9525 $30.00
© Sarmiento et al.
WASP family members and formin proteins coordinate regulation of cell protrusions in carcinoma cells
Corina Sarmiento1,
Weigang Wang1,
Athanassios Dovas1,
Hideki Yamaguchi1,
Mazen Sidani1,
Mirvat El-Sibai2,
Vera DesMarais1,
Holly A. Holman4,
Susan Kitchen4,
Jonathan M. Backer2,
Art Alberts4, and
John Condeelis1,3
1 Department of Anatomy and Structural Biology, 2 Department of Pharmacology, and 3 Gruss Lipper Center for Biophotonics, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461
4 Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, MI 49503
Correspondence to Corina Sarmiento: csarmien{at}aecom.yu.edu
We examined the role of the actin nucleation promoters neural Wiskott-Aldrich syndrome protein (N-WASP) and WAVE2 in cell protrusion in response to epidermal growth factor (EGF), a key regulator in carcinoma cell invasion. We found that WAVE2 knockdown (KD) suppresses lamellipod formation and increases filopod formation, whereas N-WASP KD has no effect. However, simultaneous KD of both proteins results in the formation of large jagged protrusions with lamellar properties and increased filopod formation. This suggests that another actin nucleation activity is at work in carcinoma cells in response to EGF. A mammalian Diaphanous–related formin, mDia1, localizes at the jagged protrusions in double KD cells. Constitutively active mDia1 recapitulated the phenotype, whereas inhibition of mDia1 blocked the formation of these protrusions. Increased RhoA activity, which stimulates mDia1 nucleation, was observed in the N-WASP/WAVE2 KD cells and was shown to be required for the N-WASP/WAVE2 KD phenotype. These data show that coordinate regulation between the WASP family and mDia proteins controls the balance between lamellar and lamellipodial protrusion activity.
Abbreviations used in this paper: Arp, actin-related protein; BE, barbed end; CRIB, Cdc42/Rac interactive binding domain; DN, dominant negative; FH2, formin homology 2; KD, knockdown; N-WASP, neural WASP; RBD, Rho binding domain; WASP, Wiskott-Aldrich syndrome protein.

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