Tyrosine Kinase-Mediated Serine Phosphorylation of Adenylyl Cyclase

详细信息    查看全文

• 作者：Christopher M. Tan ; David J. Kelvin ; David W. Litchfield ; Stephen S. G. Ferguson ; and Ross D. Feldman
• 刊名：Biochemistry
• 出版年：2001
• 出版时间：February 13, 2001
• 年：2001
• 卷：40
• 期：6
• 页码：1702 - 1709
• 全文大小：160K
• 年卷期：v.40,no.6(February 13, 2001)
• ISSN：1520-4995

文摘

Receptor tyrosine kinase (RTK) activation is associated with modulation of heptahelical receptor-stimulated adenylyl cyclase responses. The mechanisms underlying the RTK-mediated enhancement ofadenylyl cyclase function remain unclear. In the present studies, we show that the tyrosine kinase-dependentenhancement of adenylyl cyclase isoform VI function parallels an enhancement in serine phosphorylationof the enzyme. This effect was mediated by both RTK activation, with IGF-1, and by tyrosine phosphataseinhibition, with sodium orthovanadate. This enhancement of adenylyl cyclase function was not attenuatedby inhibitors of ERK, PKC, PKA, or PI3 kinase activity but was blunted by inhibition of endogenousp74^raf-1 activity. To characterize the molecular site of this effect we identified multiple candidate serineresidues in and adjacent to the adenylyl cyclase VI C1b catalytic region and performed serine-to-alaninesite-directed mutagenesis using adenylyl cyclase VI as a template. Mutation of serine residues 603 and608 or serine residues 744, 746, 750, and 754 attenuated both the tyrosine kinase-mediated enhancementof enzyme phosphorylation as well as the sensitization of function. Together, these data define a noveltyrosine kinase-mediated mechanism leading to serine phosphorylation of adenylyl cyclase isoform VIand the sensitization of adenylyl cyclase responsiveness.