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Molecular and Cellular Biology, February 2005, p. 1379-1388, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1379-1388.2005

Nm23-H1 Metastasis Suppressor Expression Level Influences the Binding Properties, Stability, and Function of the Kinase Suppressor of Ras1 (KSR1) Erk Scaffold in Breast Carcinoma Cells

Massimiliano Salerno,1* Diane Palmieri,1 Amina Bouadis,1 Douglas Halverson,1 and Patricia S. Steeg1

Women's Cancers Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland1

Received 26 July 2004/ Returned for modification 20 August 2004/ Accepted 16 November 2004

Metastatic disease is a significant contributor to cancer patient mortality. We previously reported that the Kinase Suppressor of Ras1 (KSR1) scaffold protein for the Erk mitogen-activated protein kinase pathway coimmunoprecipitated the metastasis suppressor protein Nm23-H1. We now hypothesize that altered expression levels of Nm23-H1 influence the binding properties, stability, and function of the KSR1 scaffold. Increased coimmunoprecipitation of Hsp90 with KSR1 was observed in either stable or transient transfectants of nm23-H1 in MDA-MB-435 human breast carcinoma cells. Similar trends were also observed in the cytoplasmic and nuclear fractions of cells. Cells expressing high levels of Nm23-H1 exhibited increased KSR1 degradation in the presence of either cycloheximide or an Hsp90-directed drug currently in clinical trial, 17-allylamino-17-demethoxygeldanamycin (17-AAG). In agreement with KSR1 degradation data, high-Nm23-H1-expression cells were preferentially inhibited in anchorage-independent colonization assays by 17-AAG. KSR1 scaffold binding patterns are dynamic in both the cytoplasmic and nuclear compartments, modulated by metastasis suppressor expression. Metastasis suppressor expression levels can impact traditional signaling pathways, such as the Erk pathway, resulting in altered tumor cell sensitivity to cancer therapeutics.

* Corresponding author. Mailing address: Women's Cancers Section, Laboratory of Pathology, Building 10, Room 2A33, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 594-0701. Fax: (301) 402-8910. E-mail: maxsal{at}mail.nih.gov.

Molecular and Cellular Biology, February 2005, p. 1379-1388, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1379-1388.2005




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