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Molecular and Cellular Biology, December 2009, p. 6462-6472, Vol. 29, No. 24
0270-7306/09/$08.00+0     doi:10.1128/MCB.00941-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Transforming Potential of Src Family Kinases Is Limited by the Cholesterol-Enriched Membrane Microdomain{triangledown}

Chitose Oneyama,1 Takuya Iino,1 Kazunobu Saito,1 Kei Suzuki,1 Akira Ogawa,2 and Masato Okada1*

Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan,1 Department for Evolutionary Biology, Max Planck Institute for Developmental Biology, Spemannstrasse 37-39, 72076 Tuebingen, Germany2

Received 17 July 2009/ Returned for modification 14 August 2009/ Accepted 30 September 2009

The upregulation of Src family kinases (SFKs) has been implicated in cancer progression, but the molecular mechanisms regulating their transforming potentials remain unclear. Here we show that the transforming ability of all SFK members is suppressed by being distributed to the cholesterol-enriched membrane microdomain. All SFKs could induce cell transformation when overexpressed in C-terminal Src kinase (Csk)-deficient fibroblasts. However, their transforming abilities varied depending on their affinity for the microdomain. c-Src and Blk, with a weak affinity for the microdomain due to a single myristate modification at the N terminus, could efficiently induce cell transformation, whereas SFKs with both myristate and palmitate modifications were preferentially distributed to the microdomain and required higher doses of protein expression to induce transformation. In contrast, disruption of the microdomain by depleting cholesterol could induce a robust transformation in Csk-deficient fibroblasts in which only a limited amount of activated SFKs was expressed. Conversely, the addition of cholesterol or recruitment of activated SFKs to the microdomain via a transmembrane adaptor, Cbp/PAG1, efficiently suppressed SFK-induced cell transformation. These findings suggest that the membrane microdomain spatially limits the transforming potential of SFKs by sequestering them away from the transforming pathways.

* Corresponding author. Mailing address: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-8297. Fax: 81-6-6879-8298. E-mail: okadam{at}biken.osaka-u.ac.jp

{triangledown} Published ahead of print on 12 October 2009.

Molecular and Cellular Biology, December 2009, p. 6462-6472, Vol. 29, No. 24
0270-7306/09/$08.00+0     doi:10.1128/MCB.00941-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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