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Papers In Press, published online ahead of print October 13, 2003
J. Biol. Chem, 10.1074/jbc.M310144200
Submitted on September 12, 2003
Revised on October 8, 2003
Accepted on October 13, 2003

Contribution of the membrane distal tyrosine in intracellular signaling by the granulocyte colony-stimulating factor-receptor

Tulene S. Kendrick, Richard J. Lipscombe, Oliver Rausch, Sandra E. Nicholson, Judith E. Layton, Lauren C. Goldie-Cregan, and Marie A. Bogoyevitch

Department of Biochemistry and Molecular Biology, University of Western Australia, Crawley, Western Australia 6009

Corresponding Author: marieb{at}cyllene.uwa.edu.au

We have evaluated the contribution of intracellular tyrosine residues of the Granulocyte Colony Stimulating Factor-Receptor (GCSF-R) to its signaling and cellular outcomes. We began with stable Baf3 cell lines overexpressing wildtype or mutant GCSF-Rs. When all four intracellular tyrosines of the GCSF-R were replaced with phenylalanine (FFFF GCSF-R), cell proliferation and survival were compromised. Replacement of only the membrane distal tyrosine (YYYF GCSF-R) also showed reduced survival following a GCSF withdrawal/replacement protocol, suggesting a role for this tyrosine. Proliferation by FFFY GCSF-R cells was attenuated by ~70%. In evaluating the biochemical steps involved in signaling, we then showed that the membrane distal tyrosine was necessary and sufficient for JNK activation. With the use of a cell-permeable JNK-inhibitory peptide, JNK was implicated in the proliferation of the FFFY GCSF-R mutant. To further define the events linking the membrane distal tyrosine and JNK activation, the SH2 domains of Shc, Grb2 and 3BP2 were shown to bind the full-length GCSF-R and a phospho-peptide encompassing the membrane distal tyrosine. When binding to variant phospho-peptides based on this membrane distal tyrosine was tested, altering the amino acids immediately following the phosphotyrosine could selectively abolish the interaction with Shc or Grb2, or the binding to both Grb2 and 3BP2. When these changes were introduced into the full-length GCSF-R and new cell lines created, only the mutant that did not interact with Grb2 and 3BP2 did not activate JNK. Our results suggest that direct binding of Shc by the GCSF-R is not essential for JNK activation.


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