Cool-1 Functions as an Essential Regulatory Node for EGF Receptor- And Src-mediated Cell Growth

Nat Cell Biol. 2006 Sep;8(9):945-56. doi: 10.1038/ncb1453. Epub 2006 Aug 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cell Proliferation*
  • Cell Transformation, Neoplastic*
  • Endocytosis
  • ErbB Receptors / physiology*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanine Nucleotide Exchange Factors / physiology*
  • Male
  • Mice
  • Mice, Nude
  • NIH 3T3 Cells
  • Neoplasm Transplantation
  • Neoplasms, Experimental / pathology
  • Oncogene Protein pp60(v-src) / biosynthesis
  • Oncogene Protein pp60(v-src) / physiology*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-cbl / metabolism
  • RNA Interference
  • Rho Guanine Nucleotide Exchange Factors
  • Signal Transduction
  • Transplantation, Heterologous
  • cdc42 GTP-Binding Protein / physiology*

Substances

  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • Rho Guanine Nucleotide Exchange Factors
  • Phosphotyrosine
  • Proto-Oncogene Proteins c-cbl
  • ErbB Receptors
  • Oncogene Protein pp60(v-src)
  • cdc42 GTP-Binding Protein
  • Cbl protein, mouse