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Molecular and Cellular Biology, August 2007, p. 5790-5805, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00778-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of Phospholipase C1 in Cell Spreading Requires Association with a ß-Pix/GIT1-Containing Complex, Leading to Activation of Cdc42 and Rac1

Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, United Kingdom

Received 3 May 2007/ Accepted 24 May 2007

The significance of multiprotein signaling complexes in cell motility is becoming increasingly important. We have previously shown that phospholipase C1 (PLC1) is critical for integrin-mediated cell spreading and motility (N. Jones et al., J. Cell Sci. 118:2695-2706, 2005). In the current study we show that, on a basement membrane-type matrix, PLC1 associates with the adaptor protein GIT1 and the Rac1/Cdc42 guanine exchange factor ß-Pix; GIT1 and ß-Pix form tight complexes independently of PLC1. The association of PLC1 with the complex requires both GIT1 and ß-Pix and the specific array region (SA) of PLC1. Mutations of PLC1 within the SA region reveal that association with this complex is essential for the phosphorylation of PLC1 and the progression to an elongated morphology after integrin engagement. Short interfering RNA (siRNA) depletion of either ß-Pix or GIT1 inhibited cell spreading in a fashion similar to that seen with siRNA against PLC1. Furthermore, siRNA depletion of PLC1, ß-Pix, or GIT1 inhibited Cdc42 and Rac1 activation, while constitutively active forms of Cdc42 or Rac1, but not RhoA, were able to rescue the elongation of these cells. Signaling of the PLC1/GIT1/ß-Pix complex to Cdc42/Rac1 was found to involve the activation of calpains, calcium-dependent proteases. Therefore, we propose that the association of PLC1 with complexes containing GIT1 and ß-Pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, PLC1 is also involved in the activation of Cdc42 and Rac1.

Published ahead of print on 11 June 2007.

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