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ARTICLESCool-1 functions as an essential regulatory node
for EGF receptor- and Src-mediated cell growthQiyu Feng1,3, Dan Baird2,3, Xu Peng1, Jianbin Wang1, Thi Ly1, Jun-Lin Guan1 and Richard A. Cerione1,2,4Cool-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 Cool1 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 vSrc 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.Overexpression or hyperactivation of EGFR has been linked to the
progression of a variety of human tumours, including different forms
of breast, lung and brain cancers13. Thus, it is important that EGF-
coupled signalling is carefully regulated. Ubiquitination targets EGFRs
for degradation that is catalysed by the Casitas B-lymphoma (Cbl )
proteins4,5. When the ubiquitin ligase activity of Cbl is compromised,
the balance between EGFR recycling to the cell surface and degradation in the lysosome is disrupted, resulting in receptor accumulation
and excessive mitogenic signalling4,6. Several studies have suggested
that Cbl is also required for receptor endocytosis5,79, either through
its ability to catalyse ubiquitination5,10 or by linking receptors to the
CIN85endophilin complex11.Cbl-catalysed ubiquitination of EGFRs is negatively regulated by the
GTPase Cdc42 (ref. 12). This is not due to a direct interaction between
Cdc42 and Cbl, but instead is mediated by Cool-1 (also known as Pix, -Pak-interactive exchange factor). Members of the Cool family of
proteins contain tandem diffuse B-cell lymphoma (Dbl) and pleckstrinhomology domains1315 and have been assumed to function as guanine
nucleotide exchange factors (GEFs)16,17. We have previously shown that
the specific GEF activity exhibited by Cool-2 (also known as -Pix) was
dependent on whether it existed as a dimer (RacGEF) or a monomer
(Rac or Cdc42GEF)18,19. However, although Cool-1 contains a unique
sequence (called T1) that prevents it from exhibiting...