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J. Biol. Chem., Vol. 275, Issue 39, 30118-30123, September 29, 2000

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p130^Cas Regulates the Activity of AND-34, a Novel Ral, Rap1, and R-Ras Guanine Nucleotide Exchange Factor^*

Takaya Gotoh^§, Dongpo Cai^§¶, Xuejun Tian, Larry A. Feig, and Adam Lerner^¶**

From the  Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, the  Department of Medicine, Section of Hematology and Oncology, Boston Medical Center, and the ^¶ Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 02118

We previously identified a novel murine protein, AND-34, with a carboxyl-terminal domain homologous to Ras family guanine nucleotide exchange factors (GEFs), which bound to the focal adhesion docking protein p130^Cas. Work by others has implicated both the human homologue of AND-34, BCAR3, and human p130^Cas, BCAR1, in the resistance of breast cancer cells to the anti-estrogen tamoxifen. Here we report that AND-34 displays GEF activity on RalA, Rap1A, and R-Ras but not Ha-Ras GTPases in cells. In contrast to several other Ral-GEFs, the Ral GEF activity of AND-34 is not augmented by constitutively active Ha-Ras^Val-12, consistent with the absence of a detectable Ras-binding domain. Efficient binding to AND-34 required both the Src-binding domain and a flanking carboxyl-terminal region of p130^Cas. The p130^Cas-binding site mapped to a carboxyl-terminal sequence within the AND-34 GEF domain. Overexpression of p130^Cas, but not an AND-34-binding mutant of p130^Cas, inhibited the Ral GEF activity of co-transfected AND-34. This work identifies a new potential function for p130^Cas and a new regulatory pathway involved in the control of Ral, Rap, and R-Ras GTPases that may participate in the progression of breast cancer cells to tamoxifen resistance.

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