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J Biol Chem, Vol. 274, Issue 7, 4166-4173, February 12, 1999

The Nuclear Cap-binding Complex Is a Novel Target of Growth Factor Receptor-coupled Signal Transduction

Kristin F. Wilson, Puri Fortes^§, Ugra S. Singh^¶, Mutsuhito Ohno^§, Iain W. Mattaj^§, and Richard A. Cerione^¶

From the Departments of  Biochemistry, Molecular and Cellular Biology and ^¶ Molecular Medicine, Cornell University, Ithaca, New York 14853 and the ^§ European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Federal Republic of Germany

In an attempt to further understand how nuclear events (such as gene expression, nuclear import/export, and cell cycle checkpoint control) might be subject to regulation by extracellular stimuli, we sought to identify nuclear activities under growth factor control. Using a sensitive photoaffinity labeling assay that measured [-³²P]GTP incorporation into nuclear proteins, we identified the 20-kDa subunit of the nuclear cap-binding complex (CBC) as a protein whose binding activity is greatly enhanced by the extracellular stimulation of serum-arrested cells. The CBC represents a 20- and 80-kDa heterodimer (the subunits independently referred to as CBP20 and CBP80, respectively) that binds the 7-methylguanosine cap on RNAs transcribed by RNA polymerase II. This binding facilitates precursor messenger RNA splicing and export. We have demonstrated that the [-³²P]GTP incorporation into CBP20 was correlated with an increased ability of the CBC to bind capped RNA and have used the [-³²P]GTP photoaffinity assay to characterize the activation of the CBC in response to growth factors. We show that the CBC is activated by heregulin in HeLa cells and by nerve growth factor in PC12 cells as well as during the G₁/S phase of the cell cycle and when cells are stressed with UV irradiation. Additionally, we show that cap-dependent splicing of precursor mRNA, a functional outcome of CBC activation, can be catalyzed by growth factor addition to serum-arrested cells. Taken together, these data identify the CBC as a nuclear target for growth factor-coupled signal transduction and suggest novel mechanisms by which growth factors can influence gene expression and cell growth.

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