Myristoylation and membrane binding regulate c-Src stability and kinase activity

Mol Cell Biol. 2010 Sep;30(17):4094-107. doi: 10.1128/MCB.00246-10. Epub 2010 Jun 28.


Myristoylation is critical for membrane association of Src kinases, but a role for myristate in regulating other aspects of Src biology has not been explored. In the c-Abl tyrosine kinase, myristate binds within a hydrophobic pocket at the base of the kinase domain and latches the protein into an autoinhibitory conformation. A similar pocket has been predicted to exist in c-Src, raising the possibility that Src might also be regulated by myristoylation. Here we show that in contrast to the case for c-Abl, myristoylation exerts a positive effect on c-Src kinase activity. We also demonstrate that myristoylation and membrane binding regulate c-Src ubiquitination and degradation. Nonmyristoylated c-Src exhibited reduced kinase activity but had enhanced stability compared to myristoylated c-Src. We then mutated critical residues in the predicted myristate binding pocket of c-Src. Mutation of L360 and/or E486 had no effect on c-Src membrane binding or localization. However, constructs containing a T456A mutation were partially released from the membrane, suggesting that mutagenesis could induce c-Src to undergo an artificial myristoyl switch. All of the pocket mutants exhibited decreased kinase activity. We concluded that myristoylation and the pocket residues regulate c-Src, but in a manner very different from that for c-Abl.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Cell Membrane / metabolism*
  • Chickens
  • Chlorocebus aethiops
  • Gene Expression Regulation
  • Myristic Acid / metabolism*
  • Protein Binding
  • Protein Stability
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Ubiquitination
  • src-Family Kinases / chemistry
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • Myristic Acid
  • Proto-Oncogene Proteins c-cbl
  • src-Family Kinases