PKN1-mediated phosphorylation of histone H3 threonine residue 12 (also labeled in literature as Thr11) enables recruitment of KDM1A (LSD1) demethylase to AR-regulated promoters KLK2 and KLK3 (PSA) (Metzger et al. 2008).

Phosphorylation of histone 3 at threonine residue T12 (also labeled in literature as T11) by PKN1 enables recruitment of demethylase KDM4C (JMJD2C) to trimethylated histone 3 at KLK2 and KLK3 promoters (Metzger et al. 2008). KDM4C specifically binds to trimethylated lysine residues (Whetstine et al. 2006).

PKN1 in complex with the activated AR (androgen receptor) binds promoters of KLK2 and KLK3 (PSA) genes (Metzger et al. 2008).

KDM4C (JMJD2C) demethylates trimethylated lysine K10 of histone 3 in nucleosomes associated with promoters of KLK2 and KLK3 (PSA) genes (Metzger et al. 2008), converting it to dimethylated lysine (Whetstine et al. 2006).

PKN1, activated by phosphorylation at threonine T774, binds activated AR (androgen receptor) and promotes transcription from AR-regulated promoters. On one hand, phosphorylated PKN1 promotes the formation of a functional complex of AR with the transcriptional coactivator NCOA2 (TIF2) (Metzger et al. 2003). On the other hand, binding of phosphorylated PKN1, in complex with the activated AR, to androgen-reponsive promoters of KLK2 and KLK3 (PSA) genes, leads to PKN1-mediated histone phosphorylation. PKN1-phosphorylated histones recruit histone demethylases KDM4C (JMJD2C) and KDM1A (LSD1), and the ensuing demethylation of histones associated with the promoter regions of KLK2 and KLK3 genes increases their transcription (Metzger et al. 2005, Metzger et al. 2008).

The family of Insulin like Growth Factor Binding Proteins (IGFBPs) share 50% amino acid identity with conserved N terminal and C terminal regions responsible for binding Insulin like Growth Factors I and II (IGF I and IGF II). Most circulating IGFs are in complexes with IGFBPs, which are believed to increase the residence of IGFs in the body, modulate availability of IGFs to target receptors for IGFs, reduce insulin like effects of IGFs, and act as signaling molecules independently of IGFs. About 75% of circulating IGFs are in 1500 220 KDa complexes with IGFBP3 and ALS. Such complexes are too large to pass the endothelial barrier. The remaining 20 25% of IGFs are bound to other IGFBPs in 40 50 KDa complexes. IGFs are released from IGF:IGFBP complexes by proteolysis of the IGFBP. IGFs become active after release, however IGFs may also have activity when still bound to some IGFBPs. IGFBP1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP1 binding stimulates IGF function. It is unknown which if any protease degrades IGFBP1. IGFBP2 is enriched in cerebrospinal fluid; its binding inhibits IGF function. IGFBP2 is not significantly degraded in circulation. IGFB3, which binds most IGF in the body is enriched in follicular fluid and found in many other tissues. IGFBP 3 may be cleaved by plasmin, thrombin, Prostate specific Antigen (PSA, KLK3), Matrix Metalloprotease-1 (MMP1), and Matrix Metalloprotease-2 (MMP2). IGFBP3 also binds extracellular matrix and binding lowers its affinity for IGFs. IGFBP3 binding stimulates the effects of IGFs. IGFBP4 acts to inhibit IGF function and is cleaved by Pregnancy associated Plasma Protein A (PAPPA) to release IGF. IGFBP5 is enriched in bone matrix; its binding stimulates IGF function. IGFBP5 is cleaved by Pregnancy Associated Plasma Protein A2 (PAPPA2), ADAM9, complement C1s from smooth muscle, and thrombin. Only the cleavage site for PAPPA2 is known. IGFBP6 is enriched in cerebrospinal fluid. It is unknown which if any protease degrades IGFBP6.