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).
View original pathway at Reactome.
Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1.''; PubMedEurope PMCScholia
Owen D, Lowe PN, Nietlispach D, Brosnan CE, Chirgadze DY, Parker PJ, Blundell TL, Mott HR.; ''Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1).''; PubMedEurope PMCScholia
Yoshinaga C, Mukai H, Toshimori M, Miyamoto M, Ono Y.; ''Mutational analysis of the regulatory mechanism of PKN: the regulatory region of PKN contains an arachidonic acid-sensitive autoinhibitory domain.''; PubMedEurope PMCScholia
Torbett NE, Casamassima A, Parker PJ.; ''Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1.''; PubMedEurope PMCScholia
Flynn P, Mellor H, Casamassima A, Parker PJ.; ''Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase.''; PubMedEurope PMCScholia
Palmer RH, Dekker LV, Woscholski R, Le Good JA, Gigg R, Parker PJ.; ''Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes.''; PubMedEurope PMCScholia
Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HR.; ''The Rac1 polybasic region is required for interaction with its effector PRK1.''; PubMedEurope PMCScholia
Hamaguchi T, Ito M, Feng J, Seko T, Koyama M, Machida H, Takase K, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T.; ''Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N.''; PubMedEurope PMCScholia
Dettori R, Sonzogni S, Meyer L, Lopez-Garcia LA, Morrice NA, Zeuzem S, Engel M, Piiper A, Neimanis S, Frödin M, Biondi RM.; ''Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1).''; PubMedEurope PMCScholia
Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB.''; PubMedEurope PMCScholia
Collazos A, Michael N, Whelan RD, Kelly G, Mellor H, Pang LC, Totty N, Parker PJ.; ''Site recognition and substrate screens for PKN family proteins.''; PubMedEurope PMCScholia
Maesaki R, Ihara K, Shimizu T, Kuroda S, Kaibuchi K, Hakoshima T.; ''The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1.''; PubMedEurope PMCScholia
Mukai H, Toshimori M, Shibata H, Takanaga H, Kitagawa M, Miyahara M, Shimakawa M, Ono Y.; ''Interaction of PKN with alpha-actinin.''; PubMedEurope PMCScholia
Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JM, Potier N, Scheidtmann KH, Buettner R, Schüle R.; ''Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation.''; PubMedEurope PMCScholia
Matsuzawa K, Kosako H, Inagaki N, Shibata H, Mukai H, Ono Y, Amano M, Kaibuchi K, Matsuura Y, Azuma I, Inagaki M.; ''Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN.''; PubMedEurope PMCScholia
Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y.; ''Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases.''; PubMedEurope PMCScholia
Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AH, Günther T, Buettner R, Schüle R.; ''LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.''; PubMedEurope PMCScholia
Zong H, Raman N, Mickelson-Young LA, Atkinson SJ, Quilliam LA.; ''Loop 6 of RhoA confers specificity for effector binding, stress fiber formation, and cellular transformation.''; PubMedEurope PMCScholia
Metzger E, Müller JM, Ferrari S, Buettner R, Schüle R.; ''A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer.''; PubMedEurope PMCScholia
Misaki K, Mukai H, Yoshinaga C, Oishi K, Isagawa T, Takahashi M, Ohsumi K, Kishimoto T, Ono Y.; ''PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division.''; PubMedEurope PMCScholia
Kato T, Gotoh Y, Hoffmann A, Ono Y.; ''Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1.''; PubMedEurope PMCScholia
Protein kinases N (PKN), also known as protein kinase C-related kinases (PKR) feature a C-terminal serine/threonine kinase domain and three RHO-binding motifs at the N-terminus. RHO GTPases RHOA, RHOB, RHOC and RAC1 bind PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zhong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated co-activator PDPK1 (PDK1) (Flynn et al. 2000, Torbett et al. 2003). PDPK1 phosphorylates PKNs on a highly conserved threonine residue in the kinase activation loop, which is a prerequisite for PKN activation. Phosphorylation of other residues might also be involved in activation (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009). PKNs are activated by fatty acids like arachidonic acid and phospholipids in vitro, but the in vivo significance of this activation remains unclear (Palmer et al. 1995, Yoshinaga et al. 1999).
PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011).
Binding of activated PKN1 to the androgen-activated AR (androgen receptor) promotes translocation of the p-T774-PKN1:AR:Androgen complex into the nucleus (Metzger et al. 2003).
Binding of PKN1 to androgen-activated AR (androgen receptor) promotes the formation of a functional complex of AR with the transcriptional coactivator NCOA2 (TIF2) (Metzger et al. 2003).
PKN1 (PRK1), recruited to promoters of KLK2 and KLK3 (PSA) genes through association with the activated androgen receptor (AR), phosphorylates promoter-bound nucleosomes on threonine residue T12 (also labeled as T11 in literature) of histone 3, creating the H3T11 mark (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).
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-mediated phosphorylation of histone H3 threonine residue T12 (also labeled in literature as Thr11) enables demethylation of histone H3 lysine K10 (also labeled in literature as K9) by demethylase KDM1A (LSD1) (Metzger et al. 2008). KDM1A acts on dimethylated and monomethylated H3K9 at AR-regulated promoters (Metzger et al. 2005), so it is shown that demethylation of dimethylated H3K9 (Me2K-10-H3) by KDM1A happens after demethylation of trimethylated H3K9 (Me3K-10-H3) by KDM4C (JMJD2C).
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).
PKN1-mediated phosphorylation of histone H3 threonine residue T12 (also labeled in literature as Thr11) enables demethylation of histone H3 lysine K10 (also labeled in literature as K9) by demethylase KDM1A (LSD1) (Metzger et al. 2008). KDM1A acts on dimethylated and monomethylated H3K9 at AR-regulated promoters (Metzger et al. 2005), so it is shown that KDM1A-mediated demethylation of monomethylated H3K9 (MeK-10-H3) happens sequentially after KDM1A-mediated demethylation of dimethylated H3K9 (Me2K-10-H3).
PKN1-facilitated demethylation of histones at promoters of KLK2 and KLK3 genes stimulates transcription of KLK2 and KLK3 (Metzger et al. 2005, Metzger et al. 2008).
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Gene:Nucleosome
with Me3K-10-H3PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011).
Annotated Interactions
Gene:Nucleosome
with Me3K-10-H3