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Association of the DF3/MUC1 Breast Cancer Antigen with Grb2 and the Sos/Ras Exchange Protein¹

Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in human breast carcinomas. Although the precise functional role of this protein remains unclear, the cytoplasmic tail contains potential tyrosine phosphorylation sites for binding to Src homology 2 (SH2) domains. In the present studies using human MCF-7 breast cancer cells, we show that tyrosine phosphorylated DF3 directly interacts with the SH2 domain of the adaptor protein Grb2. The findings indicate that a pYTNP site in DF3 is responsible for this interaction. The results also demonstrate that the DF3/Grb2 complex associates with the guanine nucleotide exchange protein Sos. Because Sos binds to the SH3 domains of Grb2 and, thereby, associates with Ras at the cell membrane, formation of a DF3/Grb2/Sos complex supports a role for DF3 in intracellular signaling.

¹ This investigation was supported by USPHS Grant CA58203 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115.

Received 5/23/95. Accepted 7/31/95.

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