MCB Accepts, published online ahead of print on 12 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00941-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Transforming potential of Src family kinases is limited by the cholesterol-enriched membrane microdomain

Chitose Oneyama, Takuya Iino, Kazunobu Saito, Kei Suzuki, Akira Ogawa, and Masato Okada^*

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

^* To whom correspondence should be addressed. Email: okadam{at}biken.osaka-u.ac.jp.

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 distributing 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.