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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 C{gamma}1 in Cell Spreading Requires Association with a ß-Pix/GIT1-Containing Complex, Leading to Activation of Cdc42 and Rac1{triangledown}

Neil P. Jones and Matilda Katan*

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 C{gamma}1 (PLC{gamma}1) 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, PLC{gamma}1 associates with the adaptor protein GIT1 and the Rac1/Cdc42 guanine exchange factor ß-Pix; GIT1 and ß-Pix form tight complexes independently of PLC{gamma}1. The association of PLC{gamma}1 with the complex requires both GIT1 and ß-Pix and the specific array region ({gamma}SA) of PLC{gamma}1. Mutations of PLC{gamma}1 within the {gamma}SA region reveal that association with this complex is essential for the phosphorylation of PLC{gamma}1 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 PLC{gamma}1. Furthermore, siRNA depletion of PLC{gamma}1, 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 PLC{gamma}1/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 PLC{gamma}1 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, PLC{gamma}1 is also involved in the activation of Cdc42 and Rac1.

* Corresponding author. Mailing address: Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, United Kingdom. Phone: 44 (207) 352 8133. Fax: 44 (207) 352 3299. E-mail: matilda.katan{at}icr.ac.uk

{triangledown} Published ahead of print on 11 June 2007.

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.



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