Abstract
The activation of the Janus-activated kinase 2 (Jak2) tyrosine kinase following ligand binding has remained incompletely characterized at the mechanistic level. We report that the peptidyl-prolyl isomerase (PPI) cyclophilin A (CypA), which is implicated in the regulation of protein conformation, is necessary for the prolactin (PRL)-induced activation of Jak2 and the progression of human breast cancer. A direct correlation was observed between the levels or activity of CypA and the extent of PRL-induced signaling and gene expression. Loss of PRLr-CypA binding, following treatment with the PPI inhibitor cyclosporine A (CsA), or overexpression of a dominant-negative PRLr mutant (P334A) resulted in a loss of PRLr/Jak2-mediated signaling. In vitro, CsA treatment of breast cancer cells inhibited their growth, motility, invasion, and soft agar colony formation. In vivo, CsA treatment of nude mice xenografted with breast cancer cells induced tumor necrosis and completely inhibited metastasis. These studies reveal that a CypA-mediated conformational change within the PRLr/Jak2 complex is required for PRL-induced transduction and function and indicate that the inhibition of prolyl isomerases may be a novel therapeutic strategy in the treatment of human breast cancer.
Highlights
Peptidyl-prolyl isomerases (PPI) are a family of enzymes that catalyze the cis-trans interconversion of imide bonds of proline residues [1]
To test whether cyclophilin A (CypA) could serve as a molecular toggle for the PRLr, the effects of manipulating CypA levels and activity on both PRL-responsive gene reporters and endogenous genes were examined in breast cancer cells (Fig. 1)
Recent analysis of the growth hormone receptor using mutagenesis and fluorescence resonance energy transfer approaches has suggested that a conformational change may occur within the receptor following ligand binding approximating the growth hormone receptor–associated Janus-activated kinase 2 (Jak2) kinases, thereby enabling their autophosphorylation and activation [20]
Summary
Peptidyl-prolyl isomerases (PPI) are a family of enzymes that catalyze the cis-trans interconversion of imide bonds of proline residues [1]. One member of this family, cyclophilin A (CypA), was initially identified as the primary cytosolic receptor of the immunosuppressive drug cyclosporine A Several lines of research have revealed that CypA and other PPIs may function as molecular signaling ‘‘switches’’ [6]. It has been shown that PPI activity promotes viral replication and infection of HIV [7], modulates Itk and Crk signaling [8, 9], regulates the pore opening of a neurotransmitter-gated ion channel [10], functions
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