Mutations of ovine and bovine placental lactogens change, in different ways, the biological activity mediated through homologous and heterologous lactogenic receptors

in Journal of Endocrinology
Authors:
D Helman
Search for other papers by D Helman in
Current site
Google Scholar
PubMed
Close
,
A Herman
Search for other papers by A Herman in
Current site
Google Scholar
PubMed
Close
,
J Paly
Search for other papers by J Paly in
Current site
Google Scholar
PubMed
Close
,
O Livnah
Search for other papers by O Livnah in
Current site
Google Scholar
PubMed
Close
,
PA Elkins
Search for other papers by PA Elkins in
Current site
Google Scholar
PubMed
Close
,
AM de Vos
Search for other papers by AM de Vos in
Current site
Google Scholar
PubMed
Close
,
J Djiane
Search for other papers by J Djiane in
Current site
Google Scholar
PubMed
Close
, and
A Gertler
Search for other papers by A Gertler in
Current site
Google Scholar
PubMed
Close
Free access

Sign up for journal news

The biological activities of ovine (o) and bovine (b) placental lactogens (PLs) and their mutated analogues were compared using several binding and in vitro bioassays. In almost all cases, the biological activities of these analogues mediated through rat (r) prolactin receptor (PRLR) showed little or no change, despite a remarkable decrease in their capacity to bind to the extracellular domain of rPRLR and despite compromised stability of the 2:1 complexes. These results indicate that mutations impairing the ability of oPL or bPL to form stable complexes with lactogenic receptors do not necessarily lead to a decrease in the biological activity, because the transient existence of the homodimeric complex is still sufficient to initiate the signal transduction. In contrast, oPL and bPL analogues completely, or almost completely, lost their ability to activate homologous PRLRs, and some of them even acted as site-2 antagonists. To explain the difference between the activity transduced through homologous and that transduced through heterologous PRLRs, we propose the novel term 'minimal time of homodimer persistence'. This concept assumes that in order to initiate the signal transduction, the associated kinase JAK2 has to be transphosphorylated and this requires a 'minimal time' of homodimer existence. In the case of homologous interaction between ruminant PLs and homologous PRLRs, this 'minimal time' is met, though the interaction with homologous PRLRs has a shorter half-life than that with heterologous PRLRs. Therefore oPL or bPL are active in cells possessing both homologous and heterologous PRLRs. Mutations of oPL or bPL lead to reduced affinity and, consequently, the 'time of homodimer persistence' is shortened. Although in the case of heterologous interaction the 'minimal time' is still sufficient to initiate the biological activity, in homologous interactions, which are already weaker than heterologous interactions, further destabilization of the complex shortens its persistence to below the 'minimal time', leading to full or partial loss of biological activity.

 

  • Collapse
  • Expand