Journal of Cellular Biochemistry 100:1100–1108 (2007) PROSPECTS Basic Fibroblast Growth Factor (FGF-2): The High Molecular Weight Forms Come of Age Pey-Jen Yu, 1 Giovanni Ferrari, 1 Aubrey C. Galloway, 1 Paolo Mignatti, 1,2 and Giuseppe Pintucci 1 * 1 The Seymour Cohn Cardiovascular Research Laboratory, Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York 2 Department of Cell Biology, New York University School of Medicine, New York, New York Abstract After over thirty years from its discovery, research on basic fibroblast growth factor (FGF-2) keeps reveal- ing new aspects of the complexity of its gene expression as it evolved in the eukaryotic organisms. The discovery of multiple forms of FGF-2 generated by alternative translation from AUG and non-canonical CUG codons on the same mRNA transcript has led to the characterization of a low molecular weight (LMW) FGF-2 form and various high molecular weight (HMW) forms (four in humans). In this review, we discuss the biochemical features and biological activities of the different FGF-2 forms. In particular, we focus on the properties that are unique to the HMW forms and its biological functions. J. Cell. Biochem. 100: 1100 – 1108, 2007. ß 2006 Wiley-Liss, Inc. Key words: fibroblast growth factor; HMW FGF-2; alternative translation; arginine methylation; nuclear growth factors Basic fibroblast growth factor, the prototypic member of a family of 22 proteins, was first purified as a heparin-binding polypeptide from bovine pituitary and subsequently character- ized as a basic protein of 18 kDa [Abraham et al., 1986]. Later identified as fibroblast growth factor-2 (FGF-2), it is a ubiquitous growth factor conserved throughout the eukaryotic world. As implied by its name, FGF-2 is a strong promoter of fibroblast proliferation; however, most of the interest in FGF-2 stems from the pleiotropic effects of its gene products. FGF-2 is one of the most potent angiogenic factors, possesses neuro-protective properties, and is implicated in vascular remodeling and tumor metastasis [Bikfalvi et al., 1997]. The analysis of the human FGF-2 cDNA sequence upstream of the 5 0 AUG revealed the existence of at least three (two in rodents) additional CUG initiation codons located on the same mRNA. These alternative initiation codons originate 22, 22.5, and 24 kDa (20.5 and 21 kDa in rodents) additional forms of FGF-2, collectively referred to as high molecu- lar weight (HMW) FGF-2, as opposed to low molecular weight (LMW, 18 kDa) FGF-2. An additional 34 kDa (30 kDa in rodents) form induced under conditions of cellular stress is generally poorly translated [Delrieu, 2000]. HMW FGF-2 forms, therefore, are colinear extensions of 18 kDa FGF-2 that contain the full LMW FGF-2 sequence. Similar to other proteins generated by alternative initiation codons on the same mRNA [Touriol et al., 2003], the various FGF-2 forms are differen- tially distributed in the cell and their subcel- lular localization controls their biological activity [Sorensen et al., 2006] (Fig. 1). In this review, we will discuss the differences in the generation, processing and localization of the FGF-2 forms. We will also focus on the unique biological functions of HMW FGF-2 and its role in human physiology and pathology. MECHANISMS OF TRANSLATION Alternative splicing of FGF-2 mRNA gener- ates FGF-2 diversity in chickens. However, despite the presence of two introns within the gene [Sorensen et al., 2006], no splice variants of ß 2006 Wiley-Liss, Inc. Grant sponsor: Seymour Cohn Foundation for Cardiovas- cular Surgery Research; Grant sponsor: NIH; Grant number: 5 R01 HL70203-01. *Correspondence to: Giuseppe Pintucci, PhD, The Seymour Cohn Cardiovascular Research Laboratory, New York University School of Medicine, 530 First Avenue, NB- 15W16, New York, NY 10016. E-mail: pintug01@med.nyu.edu Received 3 August 2006; Accepted 4 August 2006 DOI 10.1002/jcb.21116