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NEUROREGULATION AND MOTILITY

PI3K is involved in PDGF- receptor upregulation post-PDGF-BB treatment in mouse HSC

¹Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York; ²Experimental Pathology Section, Department of Clinical Investigation, Walter Reed Army Medical Center; and ³Departments of Biochemistry and Molecular Biology and Pathology, The George Washington University, Washington, District of Columbia; and ⁴Departamento de Ciencias de la Salud, División de Ciencias Básicas y de la Salud, Universidad Autónoma Metropolitana, Iztapalapa, México

Submitted 9 February 2005 ; accepted in final form 19 July 2006

Increased expression of PDGF- receptors is a landmark of hepatic stellate cell activation and transdifferentiation into myofibroblasts. However, the molecular mechanisms that regulate the fate of the receptor are lacking. Recent studies suggested that N-acetylcysteine enhances the extracellular degradation of PDGF- receptor by cathepsin B, thus suggesting that the absence of PDGF- receptors in quiescent cells is due to an active process of elimination and not to a lack of expression. In this communication we investigated further molecular mechanisms involved in PDGF- receptor elimination and reappearance after incubation with PDGF-BB. We showed that in culture-activated hepatic stellate cells there is no internal protein pool of receptor, that the protein is maximally phosphorylated by 5 min and completely degraded after 1 h by a lysosomal-dependent mechanism. Inhibition of receptor autophosphorylation by tyrphostin 1296 prevented its degradation, but several proteasomal inhibitors had no effect. We also showed that receptor reappearance is time and dose dependent, being more delayed in cells treated with 50 ng/ml (48 h) compared with 10 ng/ml (24 h).

hepatic stellate cells; phosphatidylinositol 3-kinase; platelet-derived growth factor- receptor; platelet-derived growth factor-BB

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