Sibutramine added to a behavior therapy program reduced BMI and body weight more than placebo and improved the profile of several metabolic risk factors in obese adolescents.
Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two ␣-and two -subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the -subunit of the receptor. The triple cluster in the tyrosine kinase domain of the -subunit is the earliest and major autophosphorylation site. Previous studies have shown that substitutions of these three tyrosines by phenylalanines of both insulin and IGF-I receptors practically abolish any activation of cellular signaling pathways. We have studied the effect of double tyrosine mutations on IGF-I-induced receptor autophosphorylation, activation of Shc and IRS-1 pathways, and cell proliferation and tumorigenicity. Substitution of tyrosines 1131/1135 blocks any detectable autophosphorylation, whereas substitution of tyrosines 1131/1136 or 1135/1136 only reduces autophosphorylation levels in some clones by ϳ50%. Nevertheless, all the cells expressing IGF-I receptors with double tyrosine substitutions demonstrated markedly reduced signaling through Shc and IRS-1 pathways. In addition, they were unable to respond to IGF-I-stimulated cell growth in culture, and tumor formation in nude mice was abrogated. These data suggest that the presence of tyrosine 1131 or 1135 essential for receptor autophosphorylation, whereas the presence of each of these tyrosines is necessary for a fully functional receptor.The multiple physiological actions, including cell growth and differentiation of the insulin-like growth factors (IGFs) 1 are mediated by the IGF-I receptor. While the IGF-I receptor and the structurally related insulin receptor are members of the type II receptor tyrosine kinase family, their in vivo biological functions are quite separate. Both the IGF-I and insulin receptors are heterotetrameric proteins composed of two extracellular ␣-subunits and two membrane-spanning -subunits linked by disulfide bonds (1-3). Sequences found in the ␣-subunits of each receptor are important for determining ligand specificity. The amino-terminal and carboxyl-terminal portions of the ␣ subunit of the insulin receptor are critical for high affinity insulin binding, while the cysteine-rich domain of the IGF-I receptor determines high affinity IGF-I binding (4 -6). Likewise, the -subunits contain a number of structurally distinct domains including the extracellular, transmembrane, juxtamembrane, tyrosine kinase, and carboxyl-terminal regions. Binding of ligand to the ␣-subunit activates the tyrosine kinase activity of the -subunit resulting in autophosphorylation on distinct tyrosine residues. The triple tyrosine cluster within the kinase domain (1131, 1135, and 1136 tyrosines in the IGF-I receptor and the equivalent residues in the insulin receptor; numbering system of Ullrich et al. (2)) is the earliest and major site of autophosphorylation. Phosphorylation of these three tyrosine residues is...
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