The involvement of a conserved family of RNA binding proteins in embryonic development and carcinogenesis Karina Yaniv, Joel K. Yisraeli * Department of Anatomy and Cell Biology, Hebrew University – Hadassah Medical School, POB 12272, 91121 Jerusalem, Israel Received 17 July 2001; accepted 30 November 2001 Received by R. Di Lauro Abstract Vg1 RBP is a member of a family of highly conserved proteins that appear to be involved in RNA localization, stability, and/or translational control in a wide variety of cell types and organisms. Over the last few years, the human homologs of these proteins have been found to be overexpressed in an increasing number of different kinds of cancers. Although the role of these proteins in neoplasia is not understood, results from several labs, including our own, are beginning to suggest that many of these proteins may be important in cell motility, a necessary requirement for metastasis. This paper will review these data and suggest a model for the role of Vg1 RBP and its homologs in embryonic development and carcinogenesis. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Intracellular RNA localization; Cell motility; Metastasis 1. Identification of Vg1 RBP and its homologs Vg1 RNA is localized to the vegetal cortex of Xenopus oocytes via a cis-acting element in its 3 0 untranslated region termed vegetal localization element (VLE; Mowry and Melton, 1992). A 69 kDa protein from oocyte extracts, termed Vg1 RBP, was found to bind to the VLE with high affinity and mediate its association with microtubules (Elisha et al., 1995; Schwartz et al., 1992). Cloning of Vg1 RBP revealed that it is highly related to another RNA binding protein, ZBP-1, implicated in the microfilament-mediated localization of b-actin RNA to the leading edge of migrating fibroblasts (Havin et al., 1998; Ross et al., 1997). (A protein identical to Vg1 RBP, termed Vera, thought to be associated with the endoplasmic reticulum, was cloned in parallel on the basis of its binding to the VLE (Deshler et al., 1997, 1998).) These proteins are thought to associate their target RNAs with cytoskeletal elements (perhaps via a more complex RNP particle) and thus facilitate transport, and presumably anchoring, within the cell. Over the last 4 years, it has become clear that these proteins are members of a highly conserved family of RNA binding proteins expressed in different types of embryonic as well as transformed cells, in a wide variety of organisms. All of these proteins contain 4 KH (hnRNP K homology) domains at their C-terminus, and 2 canonical RRMs (RNA recognition motifs) at their N-terminus; all of them show approximately 70% or greater identity throughout their 550–590 amino acid length (Fig. 1). In some cases, these proteins appear to be involved in RNA stability (CRD-BP; Doyle et al., 1998) or in translational repression (IMP-1–3; Nielsen et al., 1999). These three homologs (IMP-1–3) map to human chromosomes 17, 3, and 7, respectively (Doyle et al., 2000; and personal obser- vation). Sequence comparisons suggest that virtually all of the homologs identified from the various species can be classified into three distinct subfamilies, each represented by a different human homolog (Fig. 2). In this review, we will refer to these proteins as the Vg1 RBP/Vera, IMP, CRD-BP, KOC, and ZBP-1 (VICKZ) family. When discussing a particular family member, the number of the homologous IMP will be appended to the name, and a prefix added to indicate the species. Thus, the Xenopus Vg1 RBP will be referred to as xVICKZ3 (see Fig. 2). A putative Drosophila homolog has been reported, although it lacks the two N-terminal RRM domains and is only approxi- mately 47% identical in the KH domains to the vertebrate family sequences (Nielsen et al., 2000). Gene 287 (2002) 49–54 0378-1119/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S0378-1119(01)00866-6 www.elsevier.com/locate/gene Abbreviations: VLE, vegetal localization element; KH, hmRNP K homology; RRM, RNA recognition motif; VICKZ family proteins, Vg1 RBP/Vera, IMP, CRD-BP, KOC and ZBP-1; CNS, central nervous system * Corresponding author. Tel.: 1972-2-675-8434; fax: 1972-2-675-8909. E-mail address: yisraeli@cc.huji.ac.il (J.K. Yisraeli).