The insulin superfamily of growth-promoting proteins

Recently, structural analysis of the human transferrin and growth hormone (GH) amino acid sequences has unravelled that they harbor a motif identical to a pattern found in viral oncoproteins known to bind the primarily nuclear tumor suppressor retinoblastoma protein (RB). Since related signatures had previously been identified also in insulin and the two insulin-like growth factors (IGFs), the aim of the current study has been to investigate whether further hints substantiating these reported homologies can be found in silico. Here, additional similarities are presented supporting the notion of an insulin superfamily of growth-promoting proteins with dual localization in the extracellular environment and the intracellular space, particularly in the nucleus, as well as characterized by a tropism for RB. Radulescu Insulin Superfamily arXiv July 2007 2 Increasing evidence suggests that major growth-regulatory proteins employ similar amino acid information codes for directing cells towards quiescence, differentiation or proliferation. In this context, I have initially deciphered a potential for insulin, IGF-1 and IGF-2 to bind to the key cell cycle regulator and tumor suppressor RB (1), thus paralleling similar structure-function relationships in certain viral oncoproteins (2). I further predicted that, as a result of this physical interaction anticipated to take place primarily in the cell nucleus, RB would be inactivated and such mechanism may constitute an important growth-stimulatory event in both embryogenesis and oncogenesis (1). Subsequently, this presumed complex formation between insulin and RB was validated experimentally (3-6). So was the association between any of the two IGFs and an RB fragment (7) that had been proposed to represent the RB binding site for insulin, IGF-1 or IGF-2 (1). Recently, I have identified the same RB-binding motifs also in transferrin (8) and in GH (9,10). Remarkably, GH contains a putative RB-binding signature that is homologous to two sequences present in HTLV-1 Tax, a viral oncoprotein recently shown to physically interact with RB (11). This feature may be particularly interesting given the nuclear translocation (12) and oncogenic properties (13,14) of GH. Here, I reveal that the homologies between RB-binding viral oncoproteins and essential cellular factors with growth-promoting activity concern several motifs (Fig. 1), thus implying the existence of a superfamily of host proteins hitherto unknown. 46L Y D L49 ... 122L T C H E126 Ad5 E1A 12M L D L15 ... 22L Y C Y E26 HPV-16 E7 16L L G L19 ... 103L F C S E107 SV40 large T 205L I I L208 ... 307L L F N E311 HTLV-1 Tax 305L H L L308...319L L F N E323 HTLV-1 Tax 20L H Q L23 ... 52L C F S E56 human GH 225L L C L228... 353L K C D E357 human transferrin 37L C L L40 ... 64F V C G D68 human IGF-1 precursor 13L T F L16 ... 43F V C G D47 human IGF-2 precursor 13L L A L16 ... 41L V C G E45 human preproinsulin 13L Y Q L16 human insulin A-chain 17L V C G E21 human insulin B-chain Fig. 1 RB-binding amino acid motifs (LXXL and LXCXE as well as patterns related thereto whereby X stands for any amino acid) in viral oncoproteins and cellular growth factors. Crucial residues are highlighted in bold letters. Radulescu Insulin Superfamily arXiv July 2007