Development of a novel ligand that activates JAK2/STAT5 signaling through a heterodimer of prolactin receptor and growth hormone receptor

Abstract

The objective of this study was to determine if a functional heterodimer of prolactin receptor (PRLR) and growth hormone receptor (GHR) can be formed in humans. A novel ligand was designed that is composed of a GHR antagonist (B2036) and a PRLR antagonist (G129R) fused in tandem (B2036-G129R). Because both B2036 and G129R are binding site 2 inactive antagonists, the B2036-G129R fusion protein, in theory contains only two functional binding site 1s: one for GHR and one for PRLR. We examined the behavior of this chimeric ligand in cell lines known to express GHR, PRLR, or both receptors. The data presented show that B2036-G129R is inactive in IM-9 cells that express only GHR or Nb2 cells that express PRLR. In T-47D cells that coexpress PRLR and GHR, B2036-G129R activates JAK2/STAT5 signaling. These findings provide evidence that B2036-G129R is able to activate signal transduction through a heterodimer of PRLR and GHR in humans.

Keywords::

• Growth hormone
• growth hormone receptor
• prolactin
• prolactin receptor
• heterodimer

Acknowledgments

We thank Seth Tomblyn and Alison E. B. Springs for their critical reading of the manuscript.

Declaration of interest: This work was supported in part by the Endowment Fund of the Greenville Hospital System and a Susan G. Komen Foundation Grant (BCTR-0402985). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.