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Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth

Oncogene volume 18, pages 3831–3845 (1999)Cite this article

Abstract

The small Ras-related GTPase, TC10, has been classified on the basis of sequence homology to be a member of the Rho family. This family, which includes the Rho, Rac and CDC42 subfamilies, has been shown to regulate a variety of apparently diverse cellular processes such as actin cytoskeletal organization, mitogen-activated protein kinase (MAPK) cascades, cell cycle progression and transformation. In order to begin a study of TC10 biological function, we expressed wild type and various mutant forms of this protein in mammalian cells and investigated both the intracellular localization of the expressed proteins and their abilities to stimulate known Rho family-associated processes. Wild type TC10 was located predominantly in the cell membrane (apparently in the same regions as actin filaments), GTPase defective (75L) and GTP-binding defective (31N) mutants were located predominantly in cytoplasmic perinuclear regions, and a deletion mutant lacking the carboxyl terminal residues required for post-translational prenylation was located predominantly in the nucleus. The GTPase defective (constitutively active) TC10 mutant: (1) stimulated the formation of long filopodia; (2) activated c-Jun amino terminal kinase (JNK); (3) activated serum response factor (SRF)-dependent transcription; (4) activated NF-κB-dependent transcription; and (5) synergized with an activated Raf-kinase (Raf-CAAX) to transform NIH3T3 cells. In addition, wild type TC10 function is required for full H-Ras transforming potential. We demonstrate that an intact effector domain and carboxyl terminal prenylation signal are required for proper TC10 function and that TC10 signals to at least two separable downstream target pathways. In addition, TC10 interacted with the actin-binding and filament-forming protein, profilin, in both a two-hybrid cDNA library screen, and an in vitro binding assay. Taken together, these data support a classification of TC10 as a member of the Rho family, and in particular, suggest that TC10 functions to regulate cellular signaling to the actin cytoskeleton and processes associated with cell growth.

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Acknowledgements

We would like to thank Dr Angus Wilson for the pCGT vector, Dr Mindong Ren for the JNK constructs, Dr Shubha Bagrodia for the mPAK3-PBD (CRIB domain) construct, Dr Danny Manor for the CDC42 61L expression construct and Dr Isabel Novoa for many helpful discussions. This work was supported by Grant CB-100 from the American Cancer Society (MGR) and Grants CA42978, CA55008 and CA63071 (CJD). G Murphy was supported by PHS Training Grant GM07827 and P Pérez by a fellowship from the Ministerio de Educación y Ciencia, Spain. Computer work was carried out at the Research Computer Resource of New York University Medical Center, supported by NSF Grant DIR-8908095.

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Authors and Affiliations

  1. Department of Biochemistry, New York University Medical Center, New York, 10016, NY, USA

    Gretchen A Murphy, Stephanie A Jillian, Pablo Pérez de la Ossa, Peter D'Eustachio & Mark G Rush

  2. Kaplan Cancer Center, New York University Medical Center, New York, 10016, NY, USA

    Peter D'Eustachio & Mark G Rush

  3. Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7038, NC, USA

    Patricia A Solski & Channing J Der

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  1. Gretchen A Murphy
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Murphy, G., Solski, P., Jillian, S. et al. Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth. Oncogene 18, 3831–3845 (1999). https://doi.org/10.1038/sj.onc.1202758

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