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¹ Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461
² Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10021
³ Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10021
⁴ Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021

Address correspondence to Robert H. Singer, Dept. of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Tel.: (718) 430-8646. Fax: (718) 430-8697. E-mail: rhsinger{at}aecom.yu.edu

Chicken embryo fibroblasts (CEFs) localize ß-actin mRNA to their lamellae, a process important for the maintenance of cell polarity and motility. The localization of ß-actin mRNA requires a cis localization element (zipcode) and involves zipcode binding protein 1 (ZBP1), a protein that specifically binds to the zipcode. Both localize to the lamellipodia of polarized CEFs. ZBP1 and its homologues contain two NH₂-terminal RNA recognition motifs (RRMs) and four COOH-terminal hnRNP K homology (KH) domains. By using ZBP1 truncations fused to GFP in conjunction with in situ hybridization analysis, we have determined that KH domains three and four were responsible for granule formation and cytoskeletal association. When the NH₂ terminus was deleted, granules formed by the KH domains alone did not accumulate at the leading edge, suggesting a role for the NH₂ terminus in targeting transport granules to their destination. RNA binding studies were used to show that the third and fourth KH domains, not the RRM domains, bind the zipcode of ß-actin mRNA. Overexpression of the four KH domains or certain subsets of these domains delocalized ß-actin mRNA in CEFs and inhibited fibroblast motility, demonstrating the importance of ZBP1 function in both ß-actin mRNA localization and cell motility.

Key Words: RNA localization; RNA binding protein; KH domain protein; cell motility; CRD-BP

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