Department of Molecular Pharmacology and Toxicology , University of Southern California , Los Angeles 90033 .
Arch Biochem Biophys 305 : 9-16 ( 1993)
Abstract
Our previous study demonstrated an increase in tyrosine protein phosphorylation and phosphatidylinositol phosphorylation induced by oxidants , suggesting a proliferative potential for these reactive substances .
In the present study , we focus our investigation on the similarity between a redox cycling naphthoquinone and orthovanadate ( VO ) , an oxidant generator as well as a potent phosphotyrosyl phosphatase inhibitor , in growth of 3T3-L1 cells cultured in serum-free media .
Vanadate increased [ 3H]thymidine incorporation in a concentration-dependent manner .
However , in the presence of insulin , epidermal growth factor , or platelet-derived growth factor , VO synergistically augmented , by as much as fivefold , DNA synthesis stimulated by these growth factors .
An increase in the association of PI -kinase with the insulin receptor was also observed in cells treated with insulin + VO .
Expression of the c-fos gene , a marker of early nuclear event in mitogenesis induced by insulin , EGF , and PDGF , but not vasopressin , a non-tyrosine kinase-linked mitogen , was also enhanced by VO .
Flow cytometric analysis indicated an acceleration of cell cycle progression when VO and insulin were present simultaneously .
Striking similarity was observed between VO and 2,3-dimethoxy-1,4-naphthoquinone ( DMNQ ) in PI 3-kinase activation , c-fos proto-oncogene expression , and DNA synthesis , key events associated with cell growth .
Additionally , both VO and DMNQ gave rise to DMPO-.OH adduct EPR signal measured with cell suspensions .
These data support an oxidant-mediated increase in tyrosine protein phosphorylation early in the signal transduction cascade of growth factor receptors , leading to augmentation of cell proliferation .
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National Jewish Center for Immunology and Respiratory Medicine , Denver , CO 80206 .
Proc Natl Acad Sci U S A 90 : 6939-43 ( 1993)
Abstract
Ligand-stimulated autophosphorylation of the platelet-derived growth factor receptor ( PDGFR ) beta subunit creates a number of binding sites for SH2-containing proteins .
One of the PDGFR-associated proteins is a -kDa protein of unknown identity and function .
We present data indicating that the 64-kDa protein that associates with the activated PDGFR is Syp ( also called SH-PTP2 , PTP-1D , or SH-PTP3 ) , the ubiquitously expressed 64-kDa SH2-containing protein-tyrosine phosphatase .
Phosphorylation of Tyr-1009 in the C terminus of the PDGFR is required for the stable association of Syp , suggesting that phosphorylation of this residue creates a binding site for the Syp SH2 domains .
Although Syp stably associates with the PDGFR , this event is not required for PDGF-stimulated tyrosine phosphorylation of Syp .
These data raise the interesting possibility that protein-tyrosine phosphatases contribute to the intracellular relay of biological signals originating from receptor tyrosine kinases such as the PDGFR .
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Vestn Ross Akad Med Nauk 22 : 8-10 ( 1993)
Abstract
According to the type of secondary structure , cytokines are classified into three categories : alpha-spiral ( IFNs-alpha , beta , omega , gamma ; ILS-2 , 3,4,5,6,7,9 ; CSFs-G , M , GM , MGF , PDGF ) , beta-structural ( ILs-1 alpha , beta , TNFs-alpha , beta , FGF ) and ( alpha + beta)-structural proteins ( IL-8 , IFN-gamma IP-10 , PF-4 , bTG , GRO , 9E3 ) .
According to the type of tertiary structure , alpha-spiral proteins are grouped into IFN- and IL-2-like families and beta-structural ones into IL-1- , and TNF-like families .
Two subfamilies can be identified in the IFN-like family .
Theoretical and experimental evidence suggests that the genes IFNs are products of divergent or convergent evolution towards the gene of the ancient intracellular protein alpha-prothymosine , which is evolutionally in turn associated with the L7/I1 protein of two ribosomes .
It is suggested that the proteins of the immunoglobulin superfamily , including cytokine receptors descended from the ancient proteins of the unicellular organisms molecular shaperons .