The biological activity of Ras proteins is thought to be controlled by the guanine nucleotide exchange factor and the guanosine triphosphatase activating protein (GAP). Treatment of rat pheochromocytoma PC-12 cells with nerve growth factor (NGF) increased the amount of active Ras guanosine triphosphate complex and stimulated the activities of both the guanine nucleotide exchange factor and GAP. In PC-12 cells that overexpressed the tyrosine kinase encoded by the trk proto-oncogene (a component of the high-affinity NGF receptor), the NGF-induced activation of the regulatory proteins was potentiated. These results suggest that the NGF receptor system enhances the activities of both the guanine nucleotide exchange factor and GAP and that the activation of Ras might be controlled by the balance in activity between these two regulatory proteins.
The G protein-coupled 7 transmembrane (STM) chemoattractant receptors can be inactivated by heterologous desensitization. Earlier work showed that formly peptide receptor-like 1 (FPRL1), an STM receptor with low affinity for the bacterial chemotactic peptide formyl-methionylleucyl-phenylalamine (fMLF), is activated by peptide domains derived from the human immunodeficiency virus (HIV)-1 envelope glycoprotein gp120 and its activation results in desensitization and downregulation of the chemokine receptors CCR5 and CXCR4 from monocyte surfaces. This study investigated the possi- IntroductionChemokine receptors CCR5 and CXCR4 are 2 major coreceptors for human immunodeficiency virus (HIV)-1 infection and belong to the 7 transmembrane (STM), G protein-coupled receptor superfamily. 1 Such receptors are composed of 7 hydrophobic transmembrane domains, an N-terminus outside the cell surface, 3 extracellular and 3 intracellular loops, and a C-terminus in the cytoplasmic compartment. 2 The C-termini of these receptors contain serine and threonine residues which, on phosphorylation, are involved in signaling and receptor desensitization. 2,3 Agonistinduced phosphorylation of chemokine receptors, such as CCR5, can result in homologous desensitization and internalization of the receptors. 4,5 Chemokine receptors may also be subjected to "heterologous desensitization" when the cells are activated by agonists selective for unrelated STM receptors. 3 For example, activation of formyl peptide receptor (FPR), the receptor for the bacterial chemotactic peptide fMLF, effectively desensitizes a number of chemoattractant receptors, including the receptors for the chemokine interleukin (IL) 8. 3 Both homologous and heterologous desensitization results in impairment of various biologic functions of chemokine receptors in response to further stimulation by their cognate ligands. 3 Because human leukocytes express a variety of chemoattractant receptors, the "cross-talk" among those receptors has been proposed to be important in fine-tuning of cell responses in the presence of multiple stimulants.Two STM receptors that can be activated by the bacterial chemotactic peptide fMLF have been identified and cloned. 6,7 FPR interacts with low concentrations of fMLF and thus acts as a high-affinity fMLF receptor. On the other hand, the low-affinity variant receptor formyl peptide receptor-like 1 (FPRL1) exhibits Ca ϩϩ flux only in response to high concentrations of fMLF. 6,7 Despite the fact that both FPR and FPRL1 are among the earliest chemoattractant receptors discovered on human phagocytic leukocytes, their biologic significance in host defense and immune responses is not clear. Although the nature of the host-derived ligands for FPR remains obscure, at least 2 endogenous molecules in humans, the lipid metabolite lipoxin A4 (LXA4) 8 and a chemotactic acute-phase protein serum amyloid A (SAA), 9 have been found to activate FPRL1. HIV-1 envelope glycoprotein gp120 and gp41 also contain domains that preferentially activate either FPR or FPRL1. ...
Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells ( March 20, 1995) ABSTRACT mSOS, a guanine nucleotide exchange factor, is a positive regulator of Ras. Fyn tyrosine protein kinase is a potential mediator in T-cell antigen receptor signal transduction in subsets of T cells. We investigated the functional and physical interaction between mSOS and Fyn in T-cell hybridoma cells. Stimulation of the T-cell antigen receptor induced the activation of guanine nucleotide exchange activity in mSOS immunoprecipitates. Overexpression of Fyn mutants with an activated kinase mutation and with a Src homology 2 deletion mutation resulted in a stimulation and suppression of the mSOS activity, respectively. The complex formations of Fyn-Shc, Shc-Grb2, and Grb2-mSOS were detected in the activated Fyn-transformed cells, whereas the SH2 deletion mutant of Fyn failed to form a complex with mSOS. Moreover, tyrosine phosphorylation of Shc was induced by the overexpression of the activated Fyn. These findings support the idea that Fyn activates the activity of mSOS bound to Grb2 through tyrosine phosphorylation of Shc. Unlike the current prevailing model, Fyn-induced activation of Ras might involve the stimulation of the catalytic guanine nucleotide exchange activity of mSOS.
Two human hSos1 isoforms (Isf I and Isf II; Rojas et al., Oncogene 12, 2291± 2300 de®ned by the presence of a distinct 15 amino acid stretch in one of them, were compared biologically and biochemically using representative NIH3T3 transfectants overexpressing either one. We showed that hSos1-Isf II is signi®cantly more eective than hSos1-Isf I to induce proliferation or malignant transformation of rodent ®broblasts when transfected alone or in conjunction with normal H-Ras (Gly12). The hSos1-Isf II-Ras cotransfectants consistently exhibited higher saturation density, lower celldoubling times, increased focus-forming activity and higher ability to grow on semisolid medium and at low serum concentration than their hSos1-Isf I-Ras counterparts. Furthermore, the ratio of GTP/GDP bound to cellular p21 ras was consistently higher in the hSos1-Isf IItransfected clones, both under basal and stimulated conditions. However, no signi®cant dierences were detected in vivo between Isf I-and Isf II-transfected clones regarding the amount, stability and subcellular localization of Sos1-Grb2 complex, or the level of hSos1 phosphorylation upon cellular stimulation. Interestingly, direct Ras guanine nucleotide exchange activity assays in cellular lysates showed that Isf II transfectants consistently exhibited about threefold higher activity than Isf I transfectants under basal, unstimulated conditions. Microinjection into Xenopus oocytes of puri®ed peptides corresponding to the C-terminal region of both isoforms (encompassing the 15 amino acid insertion area and the ®rst Grb2-binding motif) showed that only the Isf II peptide, but not its corresponding Isf I peptide, was able to induce measurable rates of meiotic maturation, and synergyzed with insulin, but not progesterone, in induction of GVBD. Our results suggest that the increased biological potency displayed by hSos1-Isf II is due to higher intrinsic guanine nucleotide exchange activity conferred upon this isoform by the 15 a.a. insertion located in proximity to its Grb2 binding region.
Three inhibitors of human immunodeficiency virus (HIV) have been isolated and purified to homogeneity from Euphorbiaceae himalaya seeds (Gelonium multiflorum) and carnation leaves (Dianthus caryophytlus). These proteins. GAP 31 (Gelonium Anti‐HIV Protein 31 kDa) and DAPs 30 and 32 (dianthus anti‐HIV proteins, 30 and 32 kDa), inhibit HIV‐1 infection and replication in a dosc‐dependent manner with little toxicity to target cells. The therapeutic indices of these compounds are in the order 104, suggesting that they may be clinically important agents in the treatment of AIDS. The N‐terminal amino acid sequences of these proteins show little homology to those of previously described anti‐HIV proteins. The structure‐function features of these HIV inhibitors, based on the 40–60 amino acid residues of N‐terminal sequences, are examined.
We report biochemical evidence that epidermal growth factor and platelet-derived growth factor stimulate the Ras gua nucleotide exchange factor activity in quiescent NIH 3T3 cells. Moreover, the exchange activity is costutively enhanced in NIH 3T3 cells transformed by Src and ErbB2 oncogenic tyrosine protein kinases (TPKs), whereas transformation by oncogenic Mos and Raf does not alter the activity. GTPase-activating protein activity was not affected under these conditions. Overexpression of pp6O"src mutants contining activated and suppressor TPK mutations resulted in stimulation and inhibition ofthe exchange factor activity, respectively. A TPK inhibitor, genistein, prevented the activation of the exchange factor in epidermal growth factor/platelet-derived growth factor-treated cells and src-transformed cels. Furthermore, the exchange factor activity bound to an antiphosphotyrosine antibody immunalnity column. These findings suggest that the ganine nucleotide exchange factor, but not GTPase-activating protein, plays a major role in the Ras activation in cell proliferation initiated by growth factor receptor TPKs and malignant transformation by oncogenic TPKs and that tyrosine phosphorylation of either the exchange factor or a tightly bound protein(s) may mediate the activation of the exchange factr by these TPKs.
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