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Molecular and Cellular Biology, May 2009, p. 2505-2520, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.00034-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Tyrosine Phosphorylation of Grb2: Role in Prolactin/Epidermal Growth Factor Cross Talk in Mammary Epithelial Cell Growth and Differentiation{triangledown}

Eric Haines,1,2,{dagger} Parham Minoo,1,2,{dagger},{ddagger} Zhenqian Feng,1,2 Nazila Resalatpanah,1,2 Xin-Min Nie,1,2 Manuela Campiglio,3 Laura Alvarez,1,2 Eftihia Cocolakis,1 Mohammed Ridha,1,2 Mauricio Di Fulvio,4 Julian Gomez-Cambronero,4 Jean-Jacques Lebrun,1 and Suhad Ali1,2*

Hormones and Cancer Research Unit,1 Division of Hematology, Department of Medicine, McGill University, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada,2 Molecular Biology Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy,3 Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, Ohio 454354

Received 9 January 2009/ Returned for modification 13 February 2009/ Accepted 22 February 2009

Characterizing mechanisms regulating mammary cell growth and differentiation is vital, as they may contribute to breast carcinogenesis. Here, we examine a cross talk mechanism(s) downstream of prolactin (PRL), a primary differentiation hormone, and epidermal growth factor (EGF), an important proliferative factor, in mammary epithelial cell growth and differentiation. Our data indicate that EGF exerts inhibitory effects on PRL-induced cellular differentiation by interfering with Stat5a-mediated gene expression independent of the PRL-proximal signaling cascade. Additionally, our data show that PRL is a potent inhibitor of EGF-induced cell proliferation. We identify tyrosine phosphorylation of the growth factor receptor-bound protein 2 (Grb2) as a critical mechanism by which PRL antagonizes EGF-induced cell proliferation by attenuating the activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Together, our results define a novel negative cross-regulation between PRL and EGF involving the Jak2/Stat5a and Ras/MAPK pathways through tyrosine phosphorylation of Grb2.

* Corresponding author. Mailing address: Hormones and Cancer Research Unit, Department of Medicine, McGill University, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. Phone: (514) 934-1934, ext. 34863. Fax: (514) 982-0893. E-mail: suhad.ali{at}muhc.mcgill.ca

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Equal authorship.

{ddagger} Present address: Department of Pathology, University of California, San Diego, San Diego, CA 92103-8320.

Molecular and Cellular Biology, May 2009, p. 2505-2520, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.00034-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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