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Angiogenesis, Metastasis, and the Cellular Microenvironment

MUC1 Initiates Src-CrkL-Rac1/Cdc42–Mediated Actin Cytoskeletal Protrusive Motility after Ligating Intercellular Adhesion Molecule-1

¹ Department of Laboratory Medicine and Pathology, Heritage Medical Research Centre and ² Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada; and ³ ICOS Corporation, Bothell, Washington

Requests for reprints: Judith C. Hugh, Department of Laboratory Medicine and Pathology, 5B4.21 Mackenzie Health Sciences Centre, University of Alberta Hospital, Edmonton, AB, Canada T6G 2R7. Phone: 780-407-2872; Fax: 780-407-3009. E-mail: JudithHugh{at}cha.ab.ca

MUC1, a transmembrane glycoprotein of the mucin family, when aberrantly expressed on breast cancer cells is correlated with increased lymph node metastases. We have previously shown that MUC1 binds intercellular adhesion molecule-1 (ICAM-1) on surrounding accessory cells and facilitates transendothelial migration of MUC1-bearing cells. Nevertheless, the underlying molecular mechanism is still obscure. In the present study, we used a novel assay of actin cytoskeletal reorganization to show that by ligating ICAM-1, MUC1 triggers Rac1- and Cdc42-dependent actin cytoskeletal protrusive activity preferentially at the heterotypic cell-cell contact sites. Further, we show that these MUC1/ICAM-1 interaction–initiated lamellipodial and filopodial protrusions require Src family kinase and CT10 regulator of kinase like (CrkL) accompanied by the rapid formation of a Src-CrkL signaling complex at the MUC1 cytoplasmic domain. Through inhibition of Src kinase activity, we further revealed that Src is required for recruiting CrkL to the MUC1 cytoplasmic domain as well as mediating the observed actin cytoskeleton dynamics. These findings suggest a novel MUC1-Src-CrkL-Rac1/Cdc42 signaling cascade following ICAM-1 ligation, through which MUC1 regulates cytoskeletal reorganization and directed cell motility during cell migration. (Mol Cancer Res 2008;6(4):555–67)

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