The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge.
Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.
Dow
L E
LE
Cell Cycle & Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.
Kauffman
J S
JS
Caddy
J
J
Zarbalis
K
K
Peterson
A S
AS
Jane
S M
SM
Russell
S M
SM
Humbert
P O
PO
D001943:Breast Neoplasms; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009924:Organ Culture Techniques; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014945:Wound Healing; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins