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Cool-1 functions as an essential regulatory node for EGFreceptor- and Src-mediated cell growth

Nature Cell Biology volume 8, pages 945–956 (2006)Cite this article

Abstract

Cool-1 (cloned-out of library 1) has a key role in regulating epidermal growth factor receptor (EGFR) degradation. Here, we show that Cool-1 performs this function by functioning as both an upstream activator and downstream target for Cdc42. EGF-dependent phosphorylation of Cool–1 enables it to act as a nucleotide exchange factor for Cdc42 and to form a complex with the E3 ligase Cbl, thus regulating Cbl-catalysed EGFR degradation. The EGF-dependent phosphorylation is normally transient; however, Cool-1 phosphorylation is sustained in cells expressing v–Src and is essential for cellular transformation, as well as for v-Src-induced tumour formation in mice. These findings demonstrate that the regulated phosphorylation of Cool-1 is necessary to maintain the balance between normal signalling by EGFR and Src versus aberrant growth and transformation.

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Figure 1: Both Cdc42 and Cool-1 are necessary for full EGF-stimulated ERK activation.
Figure 2: EGF stimulates the phosphorylation of Cool-1.
Figure 3: Phosphorylation activates Cool-1.
Figure 4: Phosphorylated Cool-1 blocks EGFR endocytosis.
Figure 5: Cool-1 is necessary for the formation of cellular aggregates in v-Src-expressing NIH3T3 cells.
Figure 6: Cool-1 is necessary for v-Src-induced cell proliferation.
Figure 7: Phosphorylated Cool-1 enhances v-Src-induced colony formation in soft-agar and tumour formation in mice.
Figure 8: Schematic representation depicting the effects of phosphorylated Cool-1 on EGFR homeostasis.

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Acknowledgements

We acknowledge support from the National Institutes of Health. We also thank C. Westmiller for secretarial assistance.

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  1. Qiyu Feng and Dan Baird: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine, Cornell University, Ithaca, 14853, NY, USA

    Qiyu Feng, Xu Peng, Jianbin Wang, Thi Ly, Jun-Lin Guan & Richard A. Cerione

  2. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, 14853, NY, USA

    Dan Baird & Richard A. Cerione

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  1. Qiyu Feng
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Contributions

Q.F., D.B., X.P. and T.L. were responsible for experimental work. J.G. contributed reagents and helped with data analysis. R.A.C. was involved in project planning.

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Correspondence to Richard A. Cerione.

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The authors declare no competing financial interests.

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Feng, Q., Baird, D., Peng, X. et al. Cool-1 functions as an essential regulatory node for EGFreceptor- and Src-mediated cell growth. Nat Cell Biol 8, 945–956 (2006). https://doi.org/10.1038/ncb1453

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