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J. Biol. Chem., Vol. 275, Issue 46, 36021-36028, November 17, 2000

This Article Full Text Full Text (PDF) All Versions of this Article: 275/46/36021    most recent M002025200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morelli, S. Articles by Boland, R. Search for Related Content PubMed PubMed Citation Articles by Morelli, S. Articles by Boland, R. Social Bookmarking                      What's this?

Involvement of Tyrosine Kinase Activity in 1,25(OH)₂-vitamin D₃ Signal Transduction in Skeletal Muscle Cells^*

Susana Morelli, Claudia Buitrago, Guillermo Vazquez, Ana R. De Boland, and Ricardo Boland

From the Departamento de Biologia, Bioquimica y Farmacia, Universidad Nacional del Sur, (8000) Bahia Blanca, Argentina

In cultured chick skeletal muscle cells loaded with Fura-2, the tyrosine kinase inhibitors herbimycin A and genistein abolished both the fast inositol 1,4,5-trisphosphatedependent Ca²⁺ release from internal stores and extracellular Ca²⁺ influx induced by 1,25(OH)₂-vitamin D₃ (1,25(OH)₂D₃). Daidzein, an inactive analog of genistein, was without effects. Tyrosine phosphatase inhibition by orthovanadate increased cytosolic Ca²⁺. Anti-phosphotyrosine immunoblot analysis revealed that 1,25(OH)₂D₃ rapidly (0.5-10 min) stimulates in a concentrationdependent fashion (0.1-10 nM) tyrosine phosphorylation of several myoblast proteins, among which the major targets of the hormone could be immunochemically identified as phospholipase C (127 kDa), which mediates intracellular store Ca²⁺ mobilization and external Ca²⁺ influx, and the growth-related proteins mitogen-activated protein (MAP) kinase (42/44 kDa) and c-myc (65 kDa). Genistein suppressed the increase in phosphorylation and concomitant elevation of MAPK activity elicited by the sterol. Both genistein and the MAPK kinase (MEK) inhibitor PD98059 abolished stimulation of DNA synthesis by 1,25(OH)₂D₃. The sterol-induced increase in tyrosine phosphorylation of c-myc, a finding not reported before for cell growth regulators, was totally suppressed by the specific Src inhibitor PP1. These results demonstrate that tyrosine phosphorylation is a previously unrecognized mechanism involved in 1,25(OH)₂D₃ regulation of Ca²⁺ homeostasis in hormone target cells. In addition, the data involve tyrosine kinase cascades in the mitogenic effects of 1,25(OH)₂D₃ on skeletal muscle cells.

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