Post-translational modifications: Sumoylated on Lys-386 (major) and Lys-520. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked
polyubiquitination by RNF6 modulates AR transcriptional activity and specificity Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-534 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression.
Phosphorylation by TNK2 enhances the DNA-binding and transcriptional
activity and may be responsible for androgen-independent progression
of prostate cancer. Phosphorylation at Ser-81 by CDK9 regulates AR promoter selectivity and cell growth.
Phosphorylation by PAK6 leads to AR-mediated transcription inhibitionPalmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid
intracellular signaling via ERK and AKT kinases and cAMP generation
1Ubiquitination at Lys845, Lys847
, , , , , , Description
Androgen Receptor nuclear signaling
Androgen is the active metabolic product, 5alpha-Dihydrotestosterone , which is produced from the transformation ofTestosterone catalyzed by the
Steroid-5-alpha-reductase, alpha polypeptides 1 and 2 ( S5AR1 and S5AR2 ) , . Biological activity of androgens is mediated by binding to the Androgen receptor , a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor , .
Binding
of Testosterone or 5alpha-Dihydrotestosterone to Androgen receptor induces its dimerization, which is needed for binding to Androgen receptor 's cognate response element and recruitment of co-regulators, such as transcriptional co-activator protein E1A binding protein p300 ( p300 ), Nuclear receptor co-activators 1 and 2 ( NCOA1
(SRC1), NCOA2 (GRIP1/TIF2) ) . Androgen receptor with co-regulators induces expression of target genes, such as Prostate specific antigen Kallikrein-related peptidase 3 ( Kallikrein 3 (PSA) ) in prostate , cyclin-dependent kinase inhibitor
Cyclin-dependent kinase inhibitor 1A (p21 ) , Ezrin ( VIL2(ezrin) ) , Matrix metalloproteinase 2 ( MMP-2 ) and SREBF chaperone ( SCAP ) . Besides co-activators, Androgen receptor can also recruit co-repressors such as Cyclin D1 , RAD9 homologs ( RAD9 ) , Nuclear receptor co-repressor 1
( N-CoR ) and others.
Androgen receptor activity is tightly regulated by distinct growth factor cascades, which can induce Androgen receptor modifications, including phosphorylation and acetylation or changes in interactions of Androgen receptor with other cofactors. Epidermal growth factor ( EGF), Insulin-like growth factor 1 ( IGF-1 ), Interleukin-6 ( IL-6 ) and ligands stimulating the Protein kinase A, cAMP-dependent ( PKA-cat (cAMP-dependent) ) pathways activate Androgen receptor by phosphorylation in the absence of androgens either directly or indirectly via mitogen-activated protein kinase (MAPK) cascade and other signaling pathways in certain prostate cancer cells and, thereby, contribute
to Androgen receptor -induced gene expression .
Binding of IGF-1 ligands to Insulin-like growth factor 1 receptor ( IGF-1 receptor ) leads to activation of MAPK cascade. Phosphorylated IGF-1 receptor can directly interact with and phosphorylate adaptor protein SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ), resulting in the recruitment of the complex containing Growth factor receptor-bound protein 2 ( GRB2 ) and Son of sevenless homolog ( SOS ) and activation of small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog
( H-Ras ), v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), and the MAPK cascade Mitogen-activated protein kinase kinase 1 ( MEK1(MAP2K1) )/
Mitogen-activated protein kinase 1 ( ERK2(MAPK1) ) .
ERK2(MAPK1) kinase, in turn, phosphorylates and activates Androgen receptor itself and Androgen receptor co-activators such as NCOA1 (SRC1) and NCOA2 (GRIP1/TIF2) .
EGF enhances activity of Androgen receptor through activation of MAPK
cascade , .
IL-6 enhances Androgen receptor transactivation mainly via Signal transducer and activator of transcription 3 ( STAT3 ), which associates with Androgen receptor and is also able to induce Androgen receptor -mediated gene activation .
There is a cross talk between members of wingless-type MMTV integration site family ( WNT ) and androgen signaling pathways. Catenin (cadherin-associated protein), beta 1 (Beta-catenin) protein, is a critical molecular component of canonical WNT signaling, flowing through Galpha(q)-specific frizzled GPCRs and Dishevelled
( Dsh ). Beta-catenin promotes androgen signaling through binding
to Androgen receptor in a ligand-dependent fashion and the follow-up transcription activation of androgen-regulated genes , , . Glycogen synthase kinase 3 beta ( GSK3 beta ) involved in WNT signaling pathway, also functions as a repressor of Androgen receptor -mediated transactivation and cell growth via direct
phosphorylation ofAndrogen receptor .
Transforming growth factor, beta 1 ( TGF-beta 1 ) - mediated action follows a complex signaling pathway from its binding to Transforming growth factor, beta receptors 1 and II ( TGF-beta receptor type I, TGF-beta receptor type II ) and their phosphorylation to activation of transcription factor SMAD family member 3 ( SMAD3 ). SMAD3 interacts with Androgenreceptor and activate Androgen receptor transcriptional activity in context-dependent manner .
p21 protein (Cdc42/Rac)-activated kinase 6 ( PAK6 ) is a serine/threonine kinase from the p21-activated kinase family. ActivePAK6 phosphorylates Androgen receptor and inhibits its nuclear translocation .
Activation of the Phosphoinositide-3-kinase/ v-akt murine thymoma viral oncogene
homolog 1 ( AKT1 ) pathway results in AKT1-dependent phosphorylation of Androgen Receptor , suppression of Androgen receptor target genes, such as p21, and the decrease of androgen/ Androgen receptor -mediated apoptosis .
Proline-rich tyrosine kinase 2 ( Pyk2(FAK2) ) can
repress Androgen receptor transactivation via inactivation
of Androgenreceptor co-activator Transforming growth factor beta 1 induced transcript 1 ( Hic-5/ARA55 ). This inactivation may result from the direct phosphorylation of Hic-5/ARA55 by Pyk2(FAK2) at tyrosine 43, impairing the co-activator activity of Hic-5/ARA55and/or its sequestering to reduce the interaction
with Androgen receptor .
References:
1. Wilson JD
Reproduction, fertility, and development 2001;13(7-8):673-8
2. Heinlein CA, Chang C
Endocrine reviews 2004 Apr;25(2):276-308
3. Gelmann EP
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15
4. McEwan IJ
Endocrine-related cancer 2004 Jun;11(2):281-93
5. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B
Annals of the New York Academy of Sciences 2001 Dec;949:44-57
6. Kim J, Coetzee GA
Journal of cellular biochemistry 2004 Oct 1;93(2):233-41
7. Lu S, Liu M, Epner DE, Tsai SY, Tsai MJ
Molecular endocrinology (Baltimore, Md.) 1999 Mar;13(3):376-84
8. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A,
Flores-Morales A
The Journal of biological chemistry 2006 Jul 26;
9. Li BY, Liao XB, Fujito A, Thrasher JB, Shen F, Xu PY
Asian journal of andrology 2006 Aug 4;
10. Heemers H, Verrijdt G, Organe S, Claessens F, Heyns W, Verhoeven G,
Swinnen JV
The Journal of biological chemistry 2004 Jul
16;279(29):30880-7
11. Petre CE, Wetherill YB, Danielsen M, Knudsen KE
The Journal of biological chemistry 2002 Jan 18;277(3):2207-15
12. Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C
Molecular and cellular biology 2004 Mar;24(5):2202-13
13. Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R
Molecular and cellular biology 2006 Sep;26(17):6633-55
14. Culig Z
Growth factors (Chur, Switzerland) 2004 Sep;22(3):179-84
15. Rowan BG, Weigel NL, O'Malley BW
The Journal of biological chemistry 2000 Feb 11;275(6):4475-83
16. Reinikainen P, Palvimo JJ, Janne OA
Endocrinology 1996 Oct;137(10):4351-7
17. Gupta C
Molecular and cellular
endocrinology 1999 Jun 25;152(1-2):169-78
18. De Miguel F, Lee SO, Onate SA, Gao AC
Nuclear receptor
[electronic resource]. 2003 Jun 13;1(1):3
19. Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP
Molecular and cellular biology 2003 Mar;23(5):1674-87
20. Chesire DR, Isaacs WB
Endocrine-related cancer 2003 Dec;10(4):537-60
21. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC
Endocrine reviews 2005 Aug 26;
22. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C
The Journal of biological
chemistry 2004 Jul 30;279(31):32444-52
23. Kang HY, Huang KE, Chang SY, Ma WL, Lin WJ, Chang C
The Journal of biological chemistry 2002 Nov
15;277(46):43749-56
24. Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM
The Journal of biological chemistry 2004 Jan 16;279(3):1922-31
25. Lin HK, Yeh S, Kang HY, Chang C
Proceedings of the National Academy of Sciences of the United States of America 2001 Jun 19;98(13):7200-5
26. Wang X, Yang Y, Guo X, Sampson ER, Hsu CL, Tsai MY, Yeh S, Wu G, Guo Y,
Chang C
The Journal of biological chemistry 2002 May 3;277(18):15426-31
Post-translational modifications: Sumoylated on Lys-386 (major) and Lys-520. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked
polyubiquitination by RNF6 modulates AR transcriptional activity and specificity Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-534 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression.
Phosphorylation by TNK2 enhances the DNA-binding and transcriptional
activity and may be responsible for androgen-independent progression
of prostate cancer. Phosphorylation at Ser-81 by CDK9 regulates AR promoter selectivity and cell growth.
Phosphorylation by PAK6 leads to AR-mediated transcription inhibitionPalmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid
intracellular signaling via ERK and AKT kinases and cAMP generation
1Ubiquitination at Lys845, Lys847
, , , , , , Description
Androgen Receptor nuclear signaling
Androgen is the active metabolic product, 5alpha-Dihydrotestosterone , which is produced from the transformation ofTestosterone catalyzed by the
Steroid-5-alpha-reductase, alpha polypeptides 1 and 2 ( S5AR1 and S5AR2 ) , . Biological activity of androgens is mediated by binding to the Androgen receptor , a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor , .
Binding
of Testosterone or 5alpha-Dihydrotestosterone to Androgen receptor induces its dimerization, which is needed for binding to Androgen receptor 's cognate response element and recruitment of co-regulators, such as transcriptional co-activator protein E1A binding protein p300 ( p300 ), Nuclear receptor co-activators 1 and 2 ( NCOA1
(SRC1), NCOA2 (GRIP1/TIF2) ) . Androgen receptor with co-regulators induces expression of target genes, such as Prostate specific antigen Kallikrein-related peptidase 3 ( Kallikrein 3 (PSA) ) in prostate , cyclin-dependent kinase inhibitor
Cyclin-dependent kinase inhibitor 1A (p21 ) , Ezrin ( VIL2(ezrin) ) , Matrix metalloproteinase 2 ( MMP-2 ) and SREBF chaperone ( SCAP ) . Besides co-activators, Androgen receptor can also recruit co-repressors such as Cyclin D1 , RAD9 homologs ( RAD9 ) , Nuclear receptor co-repressor 1
( N-CoR ) and others.
Androgen receptor activity is tightly regulated by distinct growth factor cascades, which can induce Androgen receptor modifications, including phosphorylation and acetylation or changes in interactions of Androgen receptor with other cofactors. Epidermal growth factor ( EGF), Insulin-like growth factor 1 ( IGF-1 ), Interleukin-6 ( IL-6 ) and ligands stimulating the Protein kinase A, cAMP-dependent ( PKA-cat (cAMP-dependent) ) pathways activate Androgen receptor by phosphorylation in the absence of androgens either directly or indirectly via mitogen-activated protein kinase (MAPK) cascade and other signaling pathways in certain prostate cancer cells and, thereby, contribute
to Androgen receptor -induced gene expression .
Binding of IGF-1 ligands to Insulin-like growth factor 1 receptor ( IGF-1 receptor ) leads to activation of MAPK cascade. Phosphorylated IGF-1 receptor can directly interact with and phosphorylate adaptor protein SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ), resulting in the recruitment of the complex containing Growth factor receptor-bound protein 2 ( GRB2 ) and Son of sevenless homolog ( SOS ) and activation of small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog
( H-Ras ), v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), and the MAPK cascade Mitogen-activated protein kinase kinase 1 ( MEK1(MAP2K1) )/
Mitogen-activated protein kinase 1 ( ERK2(MAPK1) ) .
ERK2(MAPK1) kinase, in turn, phosphorylates and activates Androgen receptor itself and Androgen receptor co-activators such as NCOA1 (SRC1) and NCOA2 (GRIP1/TIF2) .
EGF enhances activity of Androgen receptor through activation of MAPK
cascade , .
IL-6 enhances Androgen receptor transactivation mainly via Signal transducer and activator of transcription 3 ( STAT3 ), which associates with Androgen receptor and is also able to induce Androgen receptor -mediated gene activation .
There is a cross talk between members of wingless-type MMTV integration site family ( WNT ) and androgen signaling pathways. Catenin (cadherin-associated protein), beta 1 (Beta-catenin) protein, is a critical molecular component of canonical WNT signaling, flowing through Galpha(q)-specific frizzled GPCRs and Dishevelled
( Dsh ). Beta-catenin promotes androgen signaling through binding
to Androgen receptor in a ligand-dependent fashion and the follow-up transcription activation of androgen-regulated genes , , . Glycogen synthase kinase 3 beta ( GSK3 beta ) involved in WNT signaling pathway, also functions as a repressor of Androgen receptor -mediated transactivation and cell growth via direct
phosphorylation ofAndrogen receptor .
Transforming growth factor, beta 1 ( TGF-beta 1 ) - mediated action follows a complex signaling pathway from its binding to Transforming growth factor, beta receptors 1 and II ( TGF-beta receptor type I, TGF-beta receptor type II ) and their phosphorylation to activation of transcription factor SMAD family member 3 ( SMAD3 ). SMAD3 interacts with Androgenreceptor and activate Androgen receptor transcriptional activity in context-dependent manner .
p21 protein (Cdc42/Rac)-activated kinase 6 ( PAK6 ) is a serine/threonine kinase from the p21-activated kinase family. ActivePAK6 phosphorylates Androgen receptor and inhibits its nuclear translocation .
Activation of the Phosphoinositide-3-kinase/ v-akt murine thymoma viral oncogene
homolog 1 ( AKT1 ) pathway results in AKT1-dependent phosphorylation of Androgen Receptor , suppression of Androgen receptor target genes, such as p21, and the decrease of androgen/ Androgen receptor -mediated apoptosis .
Proline-rich tyrosine kinase 2 ( Pyk2(FAK2) ) can
repress Androgen receptor transactivation via inactivation
of Androgenreceptor co-activator Transforming growth factor beta 1 induced transcript 1 ( Hic-5/ARA55 ). This inactivation may result from the direct phosphorylation of Hic-5/ARA55 by Pyk2(FAK2) at tyrosine 43, impairing the co-activator activity of Hic-5/ARA55and/or its sequestering to reduce the interaction
with Androgen receptor .
References:
1. Wilson JD
Reproduction, fertility, and development 2001;13(7-8):673-8
2. Heinlein CA, Chang C
Endocrine reviews 2004 Apr;25(2):276-308
3. Gelmann EP
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15
4. McEwan IJ
Endocrine-related cancer 2004 Jun;11(2):281-93
5. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B
Annals of the New York Academy of Sciences 2001 Dec;949:44-57
6. Kim J, Coetzee GA
Journal of cellular biochemistry 2004 Oct 1;93(2):233-41
7. Lu S, Liu M, Epner DE, Tsai SY, Tsai MJ
Molecular endocrinology (Baltimore, Md.) 1999 Mar;13(3):376-84
8. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A,
Flores-Morales A
The Journal of biological chemistry 2006 Jul 26;
9. Li BY, Liao XB, Fujito A, Thrasher JB, Shen F, Xu PY
Asian journal of andrology 2006 Aug 4;
10. Heemers H, Verrijdt G, Organe S, Claessens F, Heyns W, Verhoeven G,
Swinnen JV
The Journal of biological chemistry 2004 Jul
16;279(29):30880-7
11. Petre CE, Wetherill YB, Danielsen M, Knudsen KE
The Journal of biological chemistry 2002 Jan 18;277(3):2207-15
12. Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C
Molecular and cellular biology 2004 Mar;24(5):2202-13
13. Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R
Molecular and cellular biology 2006 Sep;26(17):6633-55
14. Culig Z
Growth factors (Chur, Switzerland) 2004 Sep;22(3):179-84
15. Rowan BG, Weigel NL, O'Malley BW
The Journal of biological chemistry 2000 Feb 11;275(6):4475-83
16. Reinikainen P, Palvimo JJ, Janne OA
Endocrinology 1996 Oct;137(10):4351-7
17. Gupta C
Molecular and cellular
endocrinology 1999 Jun 25;152(1-2):169-78
18. De Miguel F, Lee SO, Onate SA, Gao AC
Nuclear receptor
[electronic resource]. 2003 Jun 13;1(1):3
19. Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP
Molecular and cellular biology 2003 Mar;23(5):1674-87
20. Chesire DR, Isaacs WB
Endocrine-related cancer 2003 Dec;10(4):537-60
21. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC
Endocrine reviews 2005 Aug 26;
22. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C
The Journal of biological
chemistry 2004 Jul 30;279(31):32444-52
23. Kang HY, Huang KE, Chang SY, Ma WL, Lin WJ, Chang C
The Journal of biological chemistry 2002 Nov
15;277(46):43749-56
24. Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM
The Journal of biological chemistry 2004 Jan 16;279(3):1922-31
25. Lin HK, Yeh S, Kang HY, Chang C
Proceedings of the National Academy of Sciences of the United States of America 2001 Jun 19;98(13):7200-5
26. Wang X, Yang Y, Guo X, Sampson ER, Hsu CL, Tsai MY, Yeh S, Wu G, Guo Y,
Chang C
The Journal of biological chemistry 2002 May 3;277(18):15426-31