Mechanism of ruminant placental lactogen action: molecular and in vivo studies.
Ruminant placental lactogens (PLs) are structurally related to prolactins (PRLs) and growth hormones (GHs) and are secreted by placentae. Ruminant PLs are unusual in their capacity to bind and activate PRL and GH receptors (Rs) from other species. The present minireview summarizes several works showing that unlike in heterologous species (rat, rabbit, human), in homologous (ruminant) species, PLs act by activating PRLRs or by heterodimerizing GHRs and PRLRs, and suggests that this may be the main mechanism of PL action in vivo. Mutations impairing the ability of ovine (o)PL or bovine (b)PL to form complexes with PRLRs (but not with GHRs) do not cause loss of biological activity, because the transient existence of the homodimeric complex is still sufficient to initiate the signal transduction; however, mutants do lose their ability to activate homologous PRLRs. To explain this difference, we proposed a novel term-minimal time of homodimer persistence-which assumes that to initiate the signal transduction, a "minimal time" of homodimer existence is required for transphosphorylation of associated JAK2s. In interactions between ruminant PLs and homologous PRLRs, this minimal time is met through the interaction with homologous PRLRs, which has a shorter half-life than with heterologous PRLRs. Thus oPL or bPL are active in cells possessing both homologous and heterologous PRLRs. Mutations of PLs decrease the affinity, shortening the "time of homodimer persistence." In heterologous interactions, the minimal time is still sufficient to initiate the biological activity, whereas in homologous interactions, which in any case are weaker, further destabilization of the complex shortens its persistence below the minimal time, causing loss of biological activity.
Gertler
Arieh
A
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel. gertler@agri.huji.ac.il
Djiane
Jean
J
D000818:Animals; D005260:Female; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010928:Placental Lactogen / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011487:Protein Conformation; D011981:Receptors, Prolactin / Q000187:drug effects* / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction
D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D010928:Placental Lactogen