Two classes of receptors with distinct affinities for nerve growth factor (NGF) have been identified. The low affinity receptor (Kd approximately 10(-9) to 10(-8) M) is a cysteine-rich glycoprotein encoded by the previously characterized LNGFR gene. The structural nature of the high affinity receptor (Kd approximately 10(-11) to 10(-10) M) has yet to be established. In this study we show that the product of the human trk proto-oncogene (gp140trk) binds NGF with high affinity. Moreover, NGF could be chemically cross-linked to the endogenous gp140trk present in rat PC12 pheochromocytoma cells as well as to gp140trk ectopically expressed in mouse fibroblasts and in insect Sf9 cells. High affinity binding of NGF to gp140trk can occur in the absence of low affinity LNGFR receptors, at least in nonneural cells. Addition of NGF to PC12 cells elicits rapid phosphorylation of gp140trk on tyrosine residues and stimulates its tyrosine kinase activity. These results indicate that gp140trk is a functional NGF receptor that mediates at least some of the signal transduction processes initiated by this neurotrophic factor.
The product of the trk proto-oncogene encodes a receptor for nerve growth factor (NGF). Here we show that NGF is a powerful mitogen that can induce resting NIH 3T3 cells to enter S phase, grow in semisolid medium, and become morphologically transformed. These mitogenic effects are absolutely dependent on expression of gp140trk receptors, but do not require the presence of the previously described low affinity NGF receptor. gp140trk also serves as a receptor for the related factor neurotrophin-3 (NT-3), but not for brain-derived neurotrophic factor. Both NGF and NT-3 induce the rapid phosphorylation of gp140trk receptors and the transient expression of c-Fos proteins. However, NT-3 appears to elicit more limited mitogenic responses than NGF. These results indicate that the product of the trk proto-oncogene is sufficient to mediate signal transduction processes induced by NGF and NT-3, at least in proliferating cells.
Ras proteins must be isoprenylated at a conserved cysteine residue near the carboxyl terminus
Transcriptional activation in eukaryotes involves protein-protein interactions between regulatory transcription factors and components of the basal transcription machinery. Here we show that c-Fos, but not a related protein, Fra-1, can bind the TATA-box-binding protein (TBP) both in vitro and in vivo and that c-Fos can also interact with the transcription factor IID complex. High-affinity binding to TBP requires c-Fos activation modules which cooperate to activate transcription. One of these activation modules contains a TBP-binding motif (TBM) which was identified through its homology to TBP-binding viral The c-Fos oncoprotein is the product of an immediate-early response gene which, together with c-Jun, can activate transcription of promoters bearing AP-1-binding sites (28). The c-Fos and c-Jun proteins have a homologous bZIP DNAbinding domain which allows them to form a complex via the leucine zipper and bind DNA via the basic motif (12,18,27,35,45,46,53). In addition, c-Fos and c-Jun have a number of independently acting homologous activation domains (1,2,5,7,50). One of these contains two homologous motifs (HOB1 and HOB2) which cannot activate transcription independently but do so cooperatively when combined (50). The HOBW motif contains a recognition site for MAP kinase whose presence is essential for the activity of HOB1. In c-Jun, this site is phosphorylated by a MAP kinase-like activity both in vitro and in vivo (6, 21, 37), suggesting that phosphorylation of HOB1 is essential for its function.The c-Fos protein is a member of a family of transcription factors which are intermittently similar along their lengths. They include Fra-1, Fra-2, FosB, and FosBSF. These c-Fosrelated proteins can all bind to c-Jun and related proteins JunB and JunD, forming heterodimers which can bind to AP-1 sites. It is unclear how these c-Fos-c-Jun-related heterodimers differ in function. Discrimination may come at the level of DNA binding (44) Initiation of transcription by RNA polymerase II can be mediated by a set of basal factors which assemble at cis-acting elements such as the TATA box and the initiator (Inr) element (41). Initiation of transcription from either one of these elements can be augmented by regulatory transcription factors bound to the promoter. These activators are thought to function by forming protein-protein interactions with basal transcription factors (14). The study of viral transactivators such as VP16, ElA, Zta, and IE2 has shown that contact with the general factors TATA-box-binding protein (TBP) and transcription factor IIB (TFIIB) can be an important step in activation (9,17,23,24,30,31,40). Several cellular transcription factors, PU.1, p53, c-Myc, and E2F, have domains which bind TBP in vitro (15,16,19,49), and recently, the c-Rel protein has been shown to form a functional contact with TBP in vivo (26,54). Direct contact with TBP is not, however, the only mechanism by which regulators activate transcription. The Spl protein, for example, can associate with other components of the basal trans...
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