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Molecular & Cellular Proteomics 8:2308-2320, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

A Mediator of Rho-dependent Invasion Moonlights as a Methionine Salvage Enzyme^*,

Yukihito Kabuyama^a,b, Elizabeth S. Litman^a,c, Paul D. Templeton^a, Sandra I. Metzner^a, Eric S. Witze^a, Gretchen M. Argast^a,d, Stephen J. Langer^e, Kirsi Polvinen^a,f, Yiqun Shellman^g, Daniel Chan^h, John B. Shabbⁱ, James E. Fitzpatrick^g, Katheryn A. Resing^a,, Marcelo C. Sousa^a and Natalie G. Ahn^a,c,j

From the Departments of ^aChemistry and Biochemistry and
^eMolecular, Cellular, and Developmental Biology and
^cHoward Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309-0215,
Departments of ^gDermatology and
^hMedical Oncology, University of Colorado Health Sciences Center, Aurora, Colorado 80220, and
ⁱDepartment of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota 58202

RhoA controls changes in cell morphology and invasion associated with cancer phenotypes. Cell lines derived from melanoma tumors at varying stages revealed that RhoA is selectively activated in cells of metastatic origin. We describe a functional proteomics strategy to identify proteins regulated by RhoA and report a previously uncharacterized human protein, named "mediator of RhoA-dependent invasion (MRDI)," that is induced in metastatic cells by constitutive RhoA activation and promotes cell invasion. In human melanomas, MRDI localization correlated with stage, showing nuclear localization in nevi and early stage tumors and cytoplasmic localization with plasma membrane accentuation in late stage tumors. Consistent with its role in promoting cell invasion, MRDI localized to cell protrusions and leading edge membranes in cultured cells and was required for cell motility, tyrosine phosphorylation of focal adhesion kinase, and modulation of actin stress fibers. Unexpectedly MRDI had enzymatic function as an isomerase that converts the S-adenosylmethionine catabolite 5-methylribose 1-phosphate into 5-methylribulose 1-phosphate. The enzymatic function of MRDI was required for methionine salvage from S-adenosylmethionine but distinct from its function in cell invasion. Thus, mechanisms used by signal transduction pathways to control cell movement have evolved from proteins with ancient function in amino acid metabolism.

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