ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation

FEBS Lett. 2007 Feb 20;581(4):727-34. doi: 10.1016/j.febslet.2007.01.039. Epub 2007 Jan 25.


Activation of the neuronal receptor tyrosine kinase ALK (anaplastic lymphoma kinase) promoted the neuron-like differentiation of PC12 cells through specific activation of the ERK MAP-kinase pathway. However, the nature of primary signaling events initiated is still poorly documented. Here, we established that Shc and FRS2 adaptors were recruited and phosphorylated following antibody-based ALK activation. We further demonstrated that Shc was recruited to the consensus phosphotyrosine site NPTpY(1507) and FRS2 was likely recruited to a novel non-orthodox phosphotyrosine site within ALK. Finally, we characterized a functional role for Shc and likely FRS2 in ALK-dependant MAP-kinase activation and neuronal differentiation of PC12 cells. These findings hence open attractive perspectives concerning specific characteristics of ALK in the control of the mechanisms driving neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Anaplastic Lymphoma Kinase
  • Animals
  • Cell Differentiation*
  • Enzyme Activation
  • Humans
  • Membrane Proteins / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Molecular Sequence Data
  • Neurons / cytology
  • Neurons / enzymology
  • PC12 Cells
  • Phenotype*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism*
  • Rats
  • Receptor Protein-Tyrosine Kinases
  • Shc Signaling Adaptor Proteins
  • Signal Transduction*
  • Src Homology 2 Domain-Containing, Transforming Protein 1


  • Adaptor Proteins, Signal Transducing
  • Membrane Proteins
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, rat
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Phosphotyrosine
  • ALK protein, human
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3