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Submitted on December 18, 2006
Accepted on July 27, 2007
Flanders Interuniversity Institute for Biotechnology, Department of Medical Protein Research, Ghent University, Faculty of Medicine and Health Sciences, A. Baertsoenkaai 3, 9000 Ghent, Belgium
* To whom correspondence should be addressed. E-mail: Jan.Tavernier{at}Ugent.be.
Binding of growth hormone to its receptor induces rapid phosphorylation of conserved tyrosine motifs that function as recruitment sites for downstream signaling molecules. Using MAPPIT, a mammalian two-hybrid method, we mapped the binding sites in the growth hormone receptor for STAT5a and STAT5b, and for the negative regulators of cytokine signaling CIS and SOCS2. Y534, Y566 and Y627 are the major recruitment sites for STAT5. A non-overlapping recruitment pattern is observed for SOCS2 and CIS with positions Y487 and Y595 as major binding sites, ruling out SOCS-mediated inhibition of STAT5 activation by competition for shared binding sites. More detailed analysis revealed that CIS binding to the Y595, but not to the Y487 motif, depends on both its SH2 domain and the C-terminal part of its SOCS box, with a critical role for the CIS Y253 residue. This functional divergence of the two CIS/SOCS2 recruitment sites is also observed upon substitution of the Y+1 residue by leucine, turning the Y487, but not the Y595 motif into a functional STAT5 recruitment site.
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