Abstract
Src kinases are activated and relocalize to the cytoplasm during mitosis, but their mitotic function has remained elusive. We describe here a novel mitotic substrate of src kinases. Trask (transmembrane and associated with src kinases) is a 140 kDa type I transmembrane glycoprotein unrelated to currently known protein families. Src kinases phosphorylate Trask in vitro and mediate its mitotic hyperphosphorylation in vivo. Trask associates with both yes and src, is localized to the cell membrane during interphase, and undergoes cytoplasmic relocalization during mitosis. Overexpression of Trask leads to cell rounding and a loss of adhesion phenotype. Consistent with a function in cell adhesion, Trask interacts with a number of adhesion and matrix proteins including cadherins, syndecans, and the membrane-type serine protease 1 (MT-SP1), and is proteolytically cleaved by MT-SP1. Trask is unique among cell adhesion molecules in that it is under cell cycle regulation and thus links src kinases with the mitotic regulation of cell adhesion. This suggests a potential pathway by which hyperactive src kinases in tumors can deregulate adhesion signaling and mediate the metastatic phenotype.
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Acknowledgements
We thank Lisa Denzin and Marilyn Resh for helpful discussions and Sami Mahrus and Chris Farady for reagents and helpful discussion regarding this manuscript. This work was supported by the American Cancer Society RSG-02-139-01-CDD (MMM) and NIH CA 72006 (CSC). ASB is supported by the NIH medical scientist training grant and a fellowship from the ARCS foundation.
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The Trask sequence has been deposited in the NCBI database with Genebank accession #AY167484
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Bhatt, A., Erdjument-Bromage, H., Tempst, P. et al. Adhesion signaling by a novel mitotic substrate of src kinases. Oncogene 24, 5333–5343 (2005). https://doi.org/10.1038/sj.onc.1208582
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DOI: https://doi.org/10.1038/sj.onc.1208582
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