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Molecular and Cellular Biology, September 2005, p. 7592-7604, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7592-7604.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Molecular Scaffold Kinase Suppressor of Ras 1 (KSR1) Regulates Adipogenesis

Robert L. Kortum,1,2 Diane L. Costanzo,1 Jamie Haferbier,1 Steven J. Schreiner,1 Gina L. Razidlo,1,2 Ming-Hoi Wu,1 Deanna J. Volle,1 Toshiyuki Mori,3 Hiroshi Sakaue,3 Nina V. Chaika,1 Oleg V. Chaika,1 and Robert E. Lewis1,2*

Eppley Institute for Research in Cancer and Allied Diseases,1 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696,2 Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan3

Received 12 April 2005/ Returned for modification 13 May 2005/ Accepted 16 May 2005

Mitogen-activated protein kinase pathways are implicated in the regulation of cell differentiation, although their precise roles in many differentiation programs remain elusive. The Raf/MEK/extracellular signal-regulated kinase (ERK) kinase cascade has been proposed to both promote and inhibit adipogenesis. Here, we titrate expression of the molecular scaffold kinase suppressor of Ras 1 (KSR1) to regulate signaling through the Raf/MEK/ERK/p90 ribosomal S6 kinase (RSK) kinase cascade and show how it determines adipogenic potential. Deletion of KSR1 prevents adipogenesis in vitro, which can be rescued by introduction of low levels of KSR1. Appropriate levels of KSR1 coordinate ERK and RSK activation with C/EBPß synthesis leading to the phosphorylation and stabilization of C/EBPß at the precise moment it is required within the adipogenic program. Elevated levels of KSR1 expression, previously shown to enhance cell proliferation, promote high, sustained ERK activation that phosphorylates and inhibits peroxisome proliferator-activated receptor gamma, inhibiting adipogenesis. Titration of KSR1 expression reveals how a molecular scaffold can modulate the intensity and duration of signaling emanating from a single pathway to dictate cell fate.

* Corresponding author. Mailing address: University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, 987696 Nebraska Medical Center, Omaha, NE 68198-7696. Phone: (402) 559-8290. Fax: (402) 559-3739. E-mail: rlewis{at}unmc.edu.

Molecular and Cellular Biology, September 2005, p. 7592-7604, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7592-7604.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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