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Molecular and Cellular Biology, August 2001, p. 5488-5499, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5488-5499.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Oncogenic Ras Blocks Anoikis by Activation of a Novel Effector Pathway Independent of Phosphatidylinositol 3-Kinase

Aidan McFall,1,* Aylin Ülkü,1 Que T. Lambert,1 Andrea Kusa,1 Kelley Rogers-Graham,1 and Channing J. Der2

Lineberger Comprehensive Cancer Center1 and Department of Pharmacology,2 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Received 12 January 2001/Returned for modification 19 February 2001/Accepted 23 May 2001

Activated Ras, but not Raf, causes transformation of RIE-1 rat intestinal epithelial cells, demonstrating the importance of Raf-independent effector signaling in mediating Ras transformation. To further assess the contribution of Raf-dependent and Raf-independent function in oncogenic Ras transformation, we evaluated the mechanism by which oncogenic Ras blocks suspension-induced apoptosis, or anoikis, of RIE-1 cells. We determined that oncogenic versions of H-, K-, and N-Ras, as well as the Ras-related proteins TC21 and R-Ras, protected RIE-1 cells from anoikis. Surprisingly, our analyses of Ras effector domain mutants or constitutively activated effectors indicated that activation of Raf-1, phosphatidylinositol 3-kinase (PI3K), or RalGDS alone is not sufficient to promote Ras inhibition of anoikis. Treatment of Ras-transformed cells with the U0126 MEK inhibitor caused partial reversion to an anoikis-sensitive state, indicating that extracellular signal-regulated kinase activation contributes to inhibition of anoikis. Unexpectedly, oncogenic Ras failed to activate Akt, and treatment of Ras-transformed RIE-1 cells with the LY294002 PI3K inhibitor did not affect anoikis resistance or growth in soft agar. Thus, while important for Ras transformation of fibroblasts, PI3K may not be involved in Ras transformation of RIE-1 cells. Finally, inhibition of epidermal growth factor receptor kinase activity did not overcome Ras inhibition of anoikis, indicating that this autocrine loop essential for transformation is not involved in anoikis protection. We conclude that a PI3K- and RalGEF-independent Ras effector(s) likely cooperates with Raf to confer anoikis resistance upon RIE-1 cells, thus underscoring the complex nature by which Ras transforms cells.

* Corresponding author. Mailing address: University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599. Phone: (919) 962-1057. Fax: (919) 966-0162. E-mail: ajmcfall{at}med.unc.edu.

Molecular and Cellular Biology, August 2001, p. 5488-5499, Vol. 21, No. 16
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.16.5488-5499.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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