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Molecular and Cellular Biology, November 2009, p. 5710-5717, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00197-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mutation of the Rb1 Pathway Leads to Overexpression of mTor, Constitutive Phosphorylation of Akt on Serine 473, Resistance to Anoikis, and a Block in c-Raf Activation{triangledown} ,{dagger}

Shahenda El-Naggar,1,2,{ddagger} Yongqing Liu,1,2,{ddagger} and Douglas C. Dean1,2,3*

James Brown Cancer Center,1 Department of Ophthalmology,2 Department of Biochemistry and Molecular Biology, University of Louisville Health Sciences Center, Louisville, Kentucky 402023

Received 12 February 2009/ Returned for modification 3 April 2009/ Accepted 3 August 2009

Atk can be activated by two independent phosphorylation events. Growth factor-dependent phosphorylation of threonine 308 (Akt-308) by phosphatidylinositol 3-kinase-dependent PDK1 leads to activation of mammalian target of rapamycin (mTor) complex 1 (TORC1) and stimulation of protein synthesis. Phosphorylation on serine 473 (Akt-473) is catalyzed by mTor in a second complex (TORC2), and Akt-473 phosphorylates Foxo3a to inhibit apoptosis. Accumulation of both phosphorylated forms of Akt is frequent in cancer, and TORC2 activity is required for progression to prostate cancer with Pten mutation. Here, we link Akt-473 to the Rb1 pathway and show that mTor is overexpressed with loss of the Rb1 family pathway. This leads to constitutive Akt-473 and, in turn, phosphorylation of Foxo3a and resistance to cell adhesion-dependent apoptosis (anoikis). Additionally, Akt-473 accumulation blocks c-Raf activation, thereby preventing downstream Erk activation. This block cannot be overcome by constitutively active Ras, and it also prevents induction of the Arf tumor suppressor by Ras. These studies link inactivation of the Rb1 pathway, a hallmark of cancer, to accumulation of Akt-473, resistance to anoikis, and a block in c-Raf/Erk activation.

* Corresponding author. Mailing address: University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY 40202. Phone: (502) 852-4882. Fax: (502) 852-0691. E-mail: dcdean01{at}louisville.edu

{triangledown} Published ahead of print on 24 August 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} S.E.-N. and Y.L. contributed equally to the study.

Molecular and Cellular Biology, November 2009, p. 5710-5717, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00197-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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