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Phospholipase Cγ1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE

Abstract

Phospholipase Cγ1 (PLC-γ1) hydrolyses phosphatidylinositol-4,5-bisphosphate to the second messengers inositol-1,4,5-trisphosphate and diacylglycerol. PLC-γ1 also has mitogenic activity upon growth-factor-dependent tyrosine phophorylation1,2; however, this activity is not dependent on the phospholipase activity of PLC-γ1, but requires an SH3 domain3,4. Here, we demonstrate that PLC-γ1 acts as a guanine nucleotide exchange factor (GEF) for PIKE (phosphatidylinositol-3-OH kinase (PI(3)K) enhancer). PIKE is a nuclear GTPase that activates nuclear PI(3)K activity, and mediates the physiological activation by nerve growth factor (NGF) of nuclear PI(3)K activity5. This enzymatic activity accounts for the mitogenic properties of PLC-γ1.

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Figure 1: Binding of Myc-PIKE to different GST–SH3 domain fusion proteins.
Figure 2: The SH3 domain of PLC-γ functions as a nucleotide exchange factor for PIKE.
Figure 3: PIKE associates with PLC-γ1.
Figure 4: PLC-γ1 associates with PIKE in PC12 cells in a GDP-dependent way.
Figure 5: The SH3 domain of PLC-γ is required for the activation of PIKE and nuclear PI(3)K.

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Acknowledgements

We thank G. Carpenter and G. Shawn for some of the plasmids. This work is supported by United States Public Health Service grants (S.H.S.), and Research Scientist Award (S.H.S.).

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Correspondence to Solomon H. Snyder.

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Ye, K., Aghdasi, B., Luo, H. et al. Phospholipase Cγ1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature 415, 541–544 (2002). https://doi.org/10.1038/415541a

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