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Volume 272, Number 39, Issue of September 26, 1997 pp. 24703-24709
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Abnormal Protein Tyrosine Phosphorylation in Fibroblasts from Hyperapobetalipoproteinemia Subjects

(Received for publication, June 16, 1997, and in revised form, July 28, 1997)

Mahnaz Motevalli , Pascal J. Goldschmidt-Clermont ^§ , Donna Virgil and Peter O. Kwiterovich Jr.

From the  Lipid Research Atherosclerosis Unit, ^§ Division of Cardiology, Bernard Laboratory, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3654

The stimulatory effects of three normal human serum basic proteins (BP), BP I (M_r 14,000, pI 9.10), BP II (M_r 27, 500, pI 8.48), and BP III (M_r 55,000, pI 8.73) on cellular triglyceride and cholesterol formation require intact protein-tyrosine kinase phosphorylation (TKP). Here we examined whether there is an abnormality in TKP in cultured fibroblasts from 11 patients with hyperapobetalipoproteinemia (hyperapoB) that manifest two acylation-stimulatory defects, decreased stimulation of triglyceride synthesis by BP I but enhanced formation of cholesterol by BP II. Soluble and insoluble proteins in Triton X-100 extracts were isolated by immunoprecipitation with a monoclonal anti-phosphotyrosine antibody (MAPA) bound to agarose beads and by ultracentrifugation, respectively, from confluent fibroblasts after incubation for 24 h in supplemented serum-free and lipid-free medium (DMEM/F12). Western blots of insoluble proteins showed that group (Gp) II (M_r 36,000-55,000) and Gp III (M_r 14,000-35,000) from hyperapoB cells, grown in DMEM/F12 medium without BP, had significantly decreased reactivity to MAPA. No significant differences in reactivity to MAPA were detected between normal and hyperapoB cells for Gp I (M_r 97-120,000). BP II, but not BP I or BP III, reversed the decreased reactivity of Gp II and Gp III to MAPA in hyperapoB cells. Sodium vanadate, an inhibitor of phosphotyrosine phosphatases, did not reverse the deficiency in TKP or the 50% deficiency in the stimulation of mass triglyceride by BP I in hyperapoB cells. Tyrosine-phosphorylated Erk-2, a mitogen-activated protein kinase, identified as one of the proteins in Gp II, was significantly decreased in hyperapoB cells. These results provide further evidence for abnormal protein TKP in hyperapoB cells and suggest a possible link between atherosclerotic changes in hyperapoB patients and growth factors upstream from mitogen-activated protein kinase.

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				P. O. Kwiterovich Jr and M. Motevalli Differential Effect of Genistein on the Stimulation of Cholesterol Production by Basic Protein II in Normal and HyperapoB Fibroblasts Arterioscler. Thromb. Vasc. Biol., January 1, 1998; 18(1): 57 - 64. [Abstract] [Full Text] [PDF]