These related genes fall into 13 paralogous groups. The products of groups 1 to 8 are more similar to the fly HOX protein Antennapedia (ANTP class), while 9 to 13 are related to the fly Abdominal-B (ABD-B class).Hox gene products function as sequence-specific DNA-binding transcription factors, as evidenced by their ability to regulate natural and artificial promoters in cell culture (18,48,49,53,61,63) and in the animal embryo (3,12,21,33,45,47,51,64).Homeodomain-DNA interactions are facilitated through residues in the flexible N-terminal arm and the recognition helix in the homeodomain (20), with the majority of HOX proteins binding a TAAT core motif. Asparagine 51 in the recognition helix plays a key role in the specificity of target site recognition, both in monomeric and in heterodimeric complexes (7,8,25,41,46,62). The size of the HOX family and their relatively poor discrimination in target site recognition suggest that they may interact with cofactors.Recently, it has been shown that the affinity and specificity of DNA binding by HOX proteins is indeed augmented by cofactor interactions. HOX cofactors in mammals include PBX (15,32,39,44,47) and MEIS (37, 57), members of the TALE family (9) of homeodomain proteins. The Drosophila homologs of mammalian PBX and MEIS are Extradenticle (EXD) (50) and Homothorax (HTH) (52), respectively. In mammals, while the majority of HOX proteins interact with PBX (HOX paralogs 1 to 10) (13), only the group 9 and 10 ABD-B class HOX proteins complex with MEIS (57).We and others have shown that a conserved motif present N terminal to the homeodomain of HOX proteins (11,15,23,27,39,43,44,54,55) and residues in the homeodomain of PBX (14,15,22,31,46) contact each other within the PBX-HOX cooperative complex. These results have been confirmed and extended through the resolution of the crystal structure of the cooperative complex (41,46). Systematic deletions carried out in HOXA9 and MEIS proteins have mapped amino acids (aa) 1 to 61 in HOXA9 and a region C terminal to the homeodomain of MEIS as responsible for mediating .In addition to their interaction with HOX proteins, MEIS and PBX form stable heterodimers that cooperatively bind DNA (16). The MEIS-related protein PREP1 interacts with PBX in a similar fashion (6). This interaction requires a portion of the first 89 aa in PBX and conserved N-terminal regions of MEIS or PREP. The chimeric oncoprotein E2A-PBX (24, 40) lacks the first 89 residues of PBX1 and is unable to interact with MEIS (16).Recently, a number of groups have reported on the formation of trimeric complexes involving proteins of the HOX, PBX, and MEIS extended families. In each case, a DNAbound PBX-HOX (or HOX-like) heterodimer tethers a member of the MEIS/PREP family via protein-protein interactions. Thus, PREP1 associates with DNA-bound HOXB1 and PBX, thereby modulating transcriptional activity (6). Mutation of the PREP1 homeodomain actually improves formation of the tri-* Corresponding author. Mailing address:

IntroductionAn enhanced appreciation of uptake mechanisms and intracellular trafficking of phosphorothioate modified oligodeoxynucleotides (P-ODN) might facilitate the use of these compounds for experimental and therapeutic purposes. We addressed these issues by identifying cell surface proteins with which P-ODN specifically interact, studying P-ODN internalization mechanisms, and by tracking internalized P-ODN through the cell using immunochemical and ultrastructural techniques.

Neurotrophins signal via Trk tyrosine kinase receptors and a common receptor called p75. Nerve growth factor is the cognate ligand for TrkA, brain-derived neurotrophic factor for TrkB, and neurotrophin-3 (NT-3) for TrkC. NT-3 also binds TrkA and TrkB as a heterologous ligand. All neurotrophins bind p75, which regulates ligand affinity and Trk signals. Trk extracellular domain has five subdomains: a leucine-rich motif, two cysteinerich clusters, and immunoglobulin-like subdomains IgG-C1 and IgG-C2. The IgG-C1 subdomain is surface exposed in the tertiary structure and regulates ligandindependent activation. The IgG-C2 subdomain is less exposed but regulates cognate ligand binding and Trk activation. NT-3 as a heterologous ligand of TrkA and TrkB optimally requires the IgG-C2 but also binds other subdomains of these receptors. When p75 is co-expressed, major changes are observed; NGF-TrkA activation can occur also via the cysteine 1 subdomain, and brain-derived neurotrophic factor-TrkB activation requires the TrkB leucine-rich motif and cysteine 2 subdomains. We propose a two-site model of Trk binding and activation, regulated conformationally by the IgG-C1 subdomain. Moreover, p75 affects Trk subdomain utilization in ligand-dependent activation, possibly by conformational or allosteric control.

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