S179D prolactin: antagonistic agony!

Abstract

The aims of this review are three-fold: first, to collate what is known about the production and activities of phosphorylated prolactin (PRL), the latter largely, but not exclusively, as illustrated through the use of the molecular mimic, S179D PRL; second, to apply this and related knowledge to produce an updated model of prolactin-receptor interactions that may apply to other members of this cytokine super-family; and third, to promote a shift in the current paradigm for the development of clinically important growth antagonists. This third aim explains the title since, based on results with S179D PRL, it is proposed that agents which signal to antagonistic ends may be better therapeutics than pure antagonists-hence antagonistic agony. Since S179D PRL is not a pure antagonist, we have proposed the term selective prolactin receptor modulator (SPeRM) for this and like molecules.

Figure 1. Diagrammatic Representation of the Proposed Properties of Different Ratios of Unmodified and Phosphorylated/S179D PRL

At one extreme, the presence of only unmodified PRL results in excess cell proliferation. With increasing amounts of phosphorylated/S179D PRL, the ratio results first in normal cell proliferation and then in a degree of cell proliferation sufficient for normal cell replacement concomitant with differentiated function. At the other extreme, high concentrations of S179D PRL result in apoptosis.

Figure 2. Diagrammatic representation of signaling in response to unmodified PRL and S179D PRL

Panel 1 shows an unliganded long receptor and panel 2 shows the effect of unmodified PRL (U-PRL) at that receptor. Binding of the ligand to the second receptor in the complex, causes a rotation which results in closer proximity of the Jak molecules (J) which then transphosphorylate and phosphorylate the receptor. This recruits Stat (St) to the receptor. Tyrosine (Y inside star) phosphorylation of Stat by Jak, releases Stat from the receptor, causes dimerization of Stats and entry into the nucleus where they function as transcription factors. Transcription may be of genes associated with cell proliferation (e.g. cyclin D1) or differentiation (e.g. β-casein), although the suggestion is being made that with more tyrosine phosphorylation (larger stars), preference is for proliferative genes. Panel 3 shows that S179D PRL interacts with the same receptor, but causes a slightly different conformation of the receptor. This results in a reduction of Stat binding and tyrosine phosphorylation (smaller star), greater activation of an alternate signaling complex (A) leading to ERK (E) activation, and the generation of a molecule (green triangles) that limits Stat tyrosine phosphorylation by receptors occupied by unmodified PRL. ERK activation leads to increased Stat serine (S inside star) phosphorylation, thereby altering which sites on the DNA are utilized (less growth-promoting and more differentiative) and, in the case of β-casein, increasing half life on DNA and promoter activation. ERK activation also leads to increased stability of β-casein mRNA, diagrammed as phosphorylation of a protein bound to the poly A tail of the message. Additionally, there are other functions resulting from ERK movement into the nucleus and the phosphorylation of additional transcription factors (dark blue hexagon) which result in increased expression of the cell cycle-regulating protein, p21. Panel 4 shows how S179D PRL might interact with a short receptor causing increased activation of ERK and increased generation of the molecules that limit Stat tyrosine phosphorylation in response to unmodified PRL.