Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth.
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.
Feng
Qiyu
Q
Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
Baird
Dan
D
Peng
Xu
X
Wang
Jianbin
J
Ly
Thi
T
Guan
Jun-Lin
JL
Cerione
Richard A
RA
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004705:Endocytosis; D066246:ErbB Receptors / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology; D015688:Oncogene Protein pp60(v-src) / Q000096:biosynthesis / Q000502:physiology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D034622:RNA Interference; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D019000:Phosphotyrosine; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D015688:Oncogene Protein pp60(v-src); D020764:cdc42 GTP-Binding Protein; C493849:Cbl protein, mouse