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ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients

Oncogene volume 29, pages 2393–2403 (2010)Cite this article

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Abstract

We have previously performed an unbiased screen to identify genes whose expression is associated with the metastatic phenotype. Secondary screening of these genes using custom microarray chips identified ASAP1, a multi-domain adaptor protein with ADP-ribosylation factor-GAP activity, as being potentially involved in tumor progression. Here, we show that at least three different splice forms of ASAP1 are upregulated in rodent tumor models in a manner that correlates with metastatic potential. In human cancers, we found that ASAP1 expression is strongly upregulated in a variety of tumors in comparison with normal tissue and that this expression correlates with poor metastasis-free survival and prognosis in colorectal cancer patients. Using loss and gain of function approaches, we were able to show that ASAP1 promotes metastasis formation in vivo and stimulates tumor cell motility, invasiveness, and adhesiveness in vitro. Furthermore, we show that ASAP1 interacts with the metastasis-promoting protein h-prune and stimulates its phosphodiesterase activity. In addition, ASAP1 binds to the SH3 domains of several proteins, including SLK with which it co-immunoprecipitates. These data support the notion that ASAP1 can contribute to the dissemination of a variety of tumor types and represent a potential target for cancer therapy.

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Acknowledgements

This work was supported by grants to JPS and US from the BMBF NGFN2 CancerNet Program, to JPS from the European Union (FP6 STREP project BRECOSM, contract no. LSHC-CT-2004-503224), to MZ from AIRC 2007–2010 and to JPS and MZ from the Association for International Cancer Research (AICR, grant no. 08-0015). We thank Norma Howells and Selma Huber for animal care and Paul Randazzo, Craig Furman, and Margaret Frame for providing expression contructs. The contribution of Franziska Arlt Pia Hermann and Markus Niederstrasser is also gratefully acknowledged.

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Authors and Affiliations

  1. Forschungszentrum Karlsruhe, Institute of Genetics, Karlsruhe, Germany

    T Müller, M Rothley, D Plaumann, W Thiele, M Bauer, M Pankratz & J P Sleeman

  2. Experimental and Clinical Research Center, Charité University Medicine Berlin, at the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    U Stein

  3. Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany

    A Poletti, M Rothley, W Thiele & J P Sleeman

  4. Centro di Ingegneria Genetica e Biotecnologia Avanzate (CEINGE), Naples, Italy

    L Garzia, A Galasso & M Zollo

  5. Charité Comprehensive Cancer Center, Berlin, Germany

    P Schlag

  6. Dipartimento di Biochimica e Biotecnologie Mediche, Faculty of Biotechnological Sciences, Universita degli Studi Di Napoli ‘Federico II’, Naples, Italy

    M Zollo

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  1. T Müller
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Correspondence to J P Sleeman.

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Müller, T., Stein, U., Poletti, A. et al. ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients. Oncogene 29, 2393–2403 (2010). https://doi.org/10.1038/onc.2010.6

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