To identify structural characteristics of the closely related cell surface receptors for insulin and IGF‐I that define their distinct physiological roles, we determined the complete primary structure of the human IGF‐I receptor from cloned cDNA. The deduced sequence predicts a 1367 amino acid receptor precursor, including a 30‐residue signal peptide, which is removed during translocation of the nascent polypeptide chain. The 1337 residue, unmodified proreceptor polypeptide has a predicted Mr of 151,869, which compares with the 180,000 Mr IGF‐I receptor precursor. In analogy with the 152,784 Mr insulin receptor precursor, cleavage of the Arg‐Lys‐Arg‐Arg sequence at position 707 of the IGF‐I receptor precursor will generate alpha (80,423 Mr) and beta (70,866 Mr) subunits, which compare with approximately 135,000 Mr (alpha) and 90,000 Mr (beta) fully glycosylated subunits.

Structural features of v‐kit, the oncogene of HZ4 feline sarcoma virus, suggested that this gene arose by transduction and truncation of cellular sequences. Complementary DNA cloning of the human proto‐oncogene coding for a receptor tyrosine kinase confirmed this possibility: c‐kit encodes a transmembrane glycoprotein that is structurally related to the receptor for macrophage growth factor (CSF‐1) and the receptor for platelet‐derived growth factor. The c‐kit gene is widely expressed as a single, 5‐kb transcript, and it is localized to human chromosome 4 and to mouse chromosome 5. A c‐kit peptide antibody permitted the identification of a 145,000 dalton c‐kit gene product that is inserted in the cellular plasma membrane and is capable of self‐phosphorylation on tyrosine residues in both human glioblastoma cells and transfected mouse fibroblasts. Our results suggest that p145c‐kit functions as a cell surface receptor for an as yet unidentified ligand. Furthermore, carboxy‐ and amino‐terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v‐kit.

A novel potential cell surface receptor of the tyrosine kinase gene family has been identified and characterized by molecular cloning. Its primary sequence is very similar to that of the human epidermal growth factor receptor and the v-erbB oncogene product; the chromosomal location of the gene for this protein is coincident with the neu oncogene, which suggests that the two genes may be identical.

A Na+-and C1-coupled serotonin (5-hydroxytryptamine, SHT) transporter is expressed on human neuronal, platelet, placental, and pulmonary membranes. The brain 5HT transporter appears to be a principal site of action of therapeutic antidepressants and may mediate behavioral and/or toxic effects of cocaine and amphetamines. Oligonucleotides derived from consensus transporter sequences were used to identify human placental cDNAs highly related to the rat brain 5HT carrier. Transfection of one of these cDNAs into HeLa cells yields a high-affinity (Km = 463 nM), Na+-and Cl--dependent 5HT transport activity which can be blocked by selective 5HT transport inhibitors, including paroxetine, fluoxetine, and imipramine, and which is antagonized by cocaine and amphetamine. Sequence analysis reveals a 630-amino acid open reading frame bearing 92% identity to the cloned rat brain 5HT transporter, with identical predicted topological features and conserved sites for posttranslational modifications. Unlike the rodent, where a single mRNA appears to encode 5HT transporters, multiple hybridizing RNAs are observed in human placenta and lung. Somatic cell hybrid and in situ hybridization studies are consistent, however, with a single gene encoding the human 5HT transporter, localized to chromosome 17q11.1-17q12.The endogenous indoleamine serotonin (5-hydroxytryptamine, 5HT) is a neurotransmitter in the central and peripheral nervous system (1, 2). Following release, 5HT is actively cleared from synaptic spaces by a high-affinity (Km 0.5 ,uM), Na+-and Cl--dependent transporter localized in presynaptic neuronal membranes (3-5). Transport of serotonin is exquisitely sensitive to nanomolar concentrations of tricyclic and heterocyclic antidepressants, including imipramine, fluoxetine, and paroxetine (6), which are thought to bind directly to the 5HT carrier (7-10), presumably constituting the initial step in their therapeutic actions. In the periphery, platelet (11), placental (12), and pulmonary (13) plasma membranes exhibit a 5HT transporter whose ionic and pharmacologic sensitivities are highly similar to those described for the neuronal transporter. In particular, plasma membrane vesicle studies reveal central and peripheral 5HT carriers to be dependent upon extracellular Na+ and Cl-, stimulated by intracellular K+, and antagonized competitively by antidepressants (5, 11, 14-17). These properties serve to distinguish the plasma membrane 5HT transporter from the monoamine transporter present in intracellular secretory vesicles, which utilizes a transmembrane H+ gradient in an imipramine-insensitive, but reserpine-sensitive, manner to sequester amines, including 5HT, for release (18).The therapeutic utility of 5HT transport antagonists in the treatment of depression, obsessive-compulsive disorder, and sleep and eating disorders (19) has contributed to an emphasis on central serotonergic dysfunction within the monoamine theory of affective disorders (20). While not a universal finding, reported reductions in platelet or brain 5H...

The primary structure of the receptor for platelet-derived growth factor (PDGF), determined by means of cloning a cDNA that encodes the murine pre-PDGF receptor, is closely related to that of the v-kit oncogene product and the receptor for macrophage colony stimulating factor (CSF-1). Common structural features include the presence of long sequences that interrupt the tyrosine-specific protein kinase domains of each molecule. The PDGF and CSF-1 receptors also share a characteristic distribution of extracellular cysteine residues. Ubiquitin is covalently bound to the purified PDGF receptor, the human gene for which is on chromosome 5.