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Objective: To determine the prevalence and clinical significance of normal, variant, and anomalous branching patterns of the aortic arch and the central veins on computed tomographic (CT) angiography in adults.Methods: We retrospectively reviewed 1000 consecutive CT angiograms of the chest in 658 women and 342 men with a median age of 53 years.Results: A total of 65.9% of patients had both normal aortic arch branching patterns and normal venous anatomy. Variants in the aortic arch branching pattern were present in 32.4% and anomalies in 1.5%. Venous anomalies were present in 0.7%. Review of CT reports showed that cardiothoracic radiologists correctly reported the anomaly more frequently than other radiologists (94% vs 20%, P = 0.003).Conclusions: Whereas anomalies of the central thoracic vasculature are uncommon, variants in the aortic arch branching pattern are common. An appreciation of the appearance of these entities on CT angiography allows for precise reporting and is useful in preprocedure planning.

Grb7, Grb10 and Grb14 comprise a family of adaptor proteins that interact with numerous receptor tyrosine kinases upon receptor activation. Between the pleckstrin homology (PH) domain and the Src homology 2 (SH2) domain of these proteins is a region of approximately 50 residues known as the BPS (between PH and SH2) domain. Here we show, using purified recombinant proteins, that the BPS domain of Grb10 directly inhibits substrate phosphorylation by the activated tyrosine kinase domains of the insulin receptor and the insulin-like growth factor 1 (IGF1) receptor. Although inhibition by the BPS domain is dependent on tyrosine phosphorylation of the kinase activation loop, peptide competition experiments indicate that the BPS domain does not bind directly to phosphotyrosine. These studies provide a molecular mechanism by which Grb10 functions as a negative regulator of insulin-and/or IGF1-mediated signaling. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

Grb7, Grb10, and Grb14 are members of a distinct family of adapter proteins that interact with various receptor tyrosine kinases upon receptor activation. Proteins in this family contain several modular signaling domains including a pleckstrin homology (PH) domain, a BPS (between PH and SH2) domain, and a C-terminal Src homology 2 (SH2) domain. Although SH2 domains are typically monomeric, we show that the Grb10 SH2 domain and also full-length Grb10␥ are dimeric in solution under physiologic conditions. The crystal structure of the Grb10 SH2 domain at 1.65-Å resolution reveals a non-covalent dimer whose interface comprises residues within and flanking the C-terminal ␣ helix, which are conserved in the Grb7/ Grb10/Grb14 family but not in other SH2 domains. Val-522 in the BG loop (BG3) and Asp-500 in the EF loop (EF1) are positioned to interfere with the binding of the P؉3 residue of a phosphopeptide ligand. These structural features of the Grb10 SH2 domain will favor binding of dimeric, turn-containing phosphotyrosine sequences, such as the phosphorylated activation loops in the two ␤ subunits of the insulin and insulin-like growth factor-1 receptors. Moreover, the structure suggests the mechanism by which the Grb7 SH2 domain binds selectively to pTyr-1139 (pYVNQ) in Her2, which along with Grb7 is co-amplified in human breast cancers.Grb10 is a member of a family of adapter proteins including Grb7 and Grb14, which have been identified as putative downstream effectors of receptor tyrosine kinases (1). Proteins in this family contain several modular domains including an Nterminal proline-rich region, a Ras-associated-like domain, a pleckstrin homology (PH) 1 domain, a short region known as the BPS (between PH and SH2) or PIR (phosphorylated insulin receptor-interacting region) domain, and a C-terminal Src homology 2 (SH2) domain. Grb10 has multiple alternatively spliced forms (␣-), which differ in their N-terminal region including the PH domain.The BPS/PIR and SH2 domains of Grb7/Grb10/Grb14 have been implicated in the interaction with activated receptor tyrosine kinases. The BPS domain is a structurally uncharacterized region of ϳ50 residues that is unique to this family of adapter proteins. The SH2 domain, found in many signaling proteins, is a well characterized protein module of ϳ100 residues that binds phosphotyrosine-containing sequences (2, 3). The BPS domains of Grb7/Grb10/Grb14 bind to the phosphorylated insulin and insulin-like growth factor-1 (IGF1) receptors (4 -6). The SH2 domains of Grb7/Grb10/Grb14 also interact with the insulin and IGF1 receptors (4, 5, 7-11) and, in addition, have been shown to mediate the interaction with the epidermal growth factor receptor (4, 12), Her2 (epidermal growth factor receptor family) (13, 14), platelet-derived growth factor receptor-␤ (10, 15, 16), Ret (17), EphB1 (18), Kit (19), Tie2 (20), and fibroblast growth factor receptor-1 (21).The roles of Grb10 family members in growth factor-mediated signaling have not been clearly established. Most studies have investigated...