EGF-induced PIP2 hydrolysis releases and activates cofilin locally in carcinoma cells.
Lamellipodial protrusion and directional migration of carcinoma cells towards chemoattractants, such as epidermal growth factor (EGF), depend upon the spatial and temporal regulation of actin cytoskeleton by actin-binding proteins (ABPs). It is generally hypothesized that the activity of many ABPs are temporally and spatially regulated by PIP(2); however, this is mainly based on in vitro-binding and structural studies, and generally in vivo evidence is lacking. Here, we provide the first in vivo data that directly visualize the spatial and temporal regulation of cofilin by PIP(2) in living cells. We show that EGF induces a rapid loss of PIP(2) through PLC activity, resulting in a release and activation of a membrane-bound pool of cofilin. Upon release, we find that cofilin binds to and severs F-actin, which is coincident with actin polymerization and lamellipod formation. Moreover, our data provide evidence for how PLC is involved in the formation of protrusions in breast carcinoma cells during chemotaxis and metastasis towards EGF.
van Rheenen
Jacco
J
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, USA. jvanrhee@aecom.yu.edu
Song
Xiaoyan
X
van Roosmalen
Wies
W
Cammer
Michael
M
Chen
Xiaoming
X
Desmarais
Vera
V
Yip
Shu-Chin
SC
Backer
Jonathan M
JM
Eddy
Robert J
RJ
Condeelis
John S
JS
D051339:Actin Depolymerizing Factors / Q000032:analysis / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006868:Hydrolysis; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000032:analysis / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats
D051339:Actin Depolymerizing Factors; D000199:Actins; D019269:Phosphatidylinositol 4,5-Diphosphate; D004815:Epidermal Growth Factor