Differential Regulation of Androgen Receptor by PIM-1 Kinases via Phosphorylation-dependent Recruitment of Distinct Ubiquitin E3 Ligases

Linn, Douglas E.; Yang, Xi; Xie, Yingqiu; Alfano, Alan P.; Deshmukh, Dhanraj; Wang, Xin; Shimelis, Hermela; Chen, Hegang; Li, Wei; Xu, Kexin; Chen, Ming‐Yuan; Qiu, Yun

doi:10.1074/jbc.m111.338350

Cited by 53 publications

(62 citation statements)

References 74 publications

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“…AKT has been reported to phosphorylate Ser213 in the AR N-terminus and thereby enhance its ubiquitylation and degradation in human PCa cells (34–36), but this effect may be cell line and passage number dependent (17, 37–39). Moreover, further studies indicate that PIM1 is the major mediator of AR Ser213 phosphorylation (40, 41), while another study found that PI3K enhanced AR stability and activity by AKT independent mechanisms (15). Studies in mice with prostate specific PTEN loss are also somewhat conflicting as one study found that PI3K pathway activation suppressed AR expression (42) while a second study found decreased AR transcriptional activity but not decreased AR expression (43).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies in human PCa cells have found that AKT can phosphorylate AR at a site in its N-terminal domain (Ser213) and thereby decrease AR transcriptional activity or enhance its ubiquitylation and degradation by MDM2 (34–36), while other studies show that AKT mediated phosphorylation of AR can increase AR protein and activity (17, 37–39). Further studies indicate that PIM1, rather than AKT, is the major mediator of AR Ser213 phosphorylation (40, 41), and that PI3K may enhance AR stability and activity by AKT independent mechanisms (15). Finally, one study in genetically engineered mice with prostate specific PTEN loss indicates that PI3K pathway activation suppresses AR expression (42), while another study found that AR transcriptional activity, but not AR expression, was decreased (43).…”

Section: Introductionmentioning

confidence: 99%

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ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer

Gao

Gerrin

et al. 2016

Clinical Cancer Research

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Purpose ErbB2 signaling appears to be increased and may enhance AR activity in a subset of CRPC, but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer (PCa), and determine whether it may contribute to androgen receptor (AR) signaling in these tumors. Experimental Design AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone, and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model. Results We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients, and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression. Conclusions ErbB2 signaling is elevated in a subset of abiraterone-resistant prostate cancer patients and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer

Gao

Gerrin

et al. 2016

Clinical Cancer Research

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“…At least two kinases, Akt and PIM-1, are known to phosphorylate S213 with different functional consequences (Wen et al 2000; Lin et al 2001; Lin et al 2003; Taneja et al 2005; Palazzolo et al 2007; Ha et al 2012; Kasina & Macoska 2012; Linn et al 2012; Varisli et al 2012). Moreover, Akt-dependent AR S213 phosphorylation is regulated by several signaling pathways (Wen et al 2000; Kasina & Macoska 2012; Varisli et al 2012).…”

Section: S213 S791 and T850 Phosphorylationmentioning

confidence: 99%

“…AR S213 was also shown to be a target for PIM-1 kinase (Linn et al 2012). PIM-1 has two isoforms, 44 kDa PIM-1L and 33 kDa PIM-1S (Saris et al 1991), both of which can directly interact with the AR and phosphorylate it at different residues, namely S213 and T850.…”

Section: S213 S791 and T850 Phosphorylationmentioning

confidence: 99%

Androgen receptor phosphorylation: biological context and functional consequences

Koryakina¹,

Ta²,

Gioeli³

2014

Endocrine-Related Cancer

121

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The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as transcription factor, but also as a node that integrates multiple extracellular signals. The importance of the AR in disease cannot be understated as it plays a role in many diseases ranging from complete androgen insensitivity syndrome to spinal bulbar muscular atrophy to prostate and breast cancer. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Fully understanding the molecular mechanisms of AR action will enable the development of future therapeutics for the wide range of AR dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine and tyrosine residues. Here we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.

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“…PIM kinases might influence self-renewal and reprogramming through direct phosphorylation of BCRP/ABCG2, a putative stem cell marker, which may be involved in multiple drug resistance57. PIM kinases might regulate androgen receptor (AR) turnover by phosphorylation58. Therefore, PIM1-dependent phosphorylation of AR regulates gene transcription, especially STAT3, which is prevalent in aggressive prostate cancer2759.…”

Section: Discussionmentioning

confidence: 99%

The role of PIM1/PIM2 kinases in tumors of the male reproductive system

Jiménez-García

Lucena-Cacace

Robles‐Frías

et al. 2016

Sci Rep

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The PIM family of serine/threonine kinases has three highly conserved isoforms (PIM1, PIM2 and PIM3). PIM proteins are regulated through transcription and stability by JAK/STAT pathways and are overexpressed in hematological malignancies and solid tumors. The PIM kinases possess weak oncogenic abilities, but enhance other genes or chemical carcinogens to induce tumors. We generated conditional transgenic mice that overexpress PIM1 or PIM2 in male reproductive organs and analyzed their contribution to tumorigenesis. We found an increase in alterations of sexual organs and hyperplasia in the transgenic mice correlating with inflammation. We also found that PIM1/2 are overexpressed in a subset of human male germ cells and prostate tumors correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression is a common feature of male reproductive organs tumors, which provoke tissue alterations and a large inflammatory response that may act synergistically during the process of tumorigenesis. There is also a correlation with markers of cancer stem cells, which may contribute to the therapy resistance found in tumors overexpressing PIM kinases.The Proviral Insertion site in Moloney murine leukemia virus proteins (PIM) are a highly evolutionarily conserved family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2 and PIM3). These proteins are regulated primarily through transcription and stability by pathways that are controlled by JAK/STAT transcription factors 1,2 , cytokines, and growth factors involved in hematopoiesis, such as interleukins, GM-CSF and G-CSF 3,4 . In addition, nuclear factor-κ B, Jak-signal transducer and activator of transcription (STAT), ETS-related gene and hypoxia-inducible factor-1α are the primary pathways that induce PIM1 upregulation [5][6][7][8] . Furthermore, the stability and function of PIM kinases depend on their interaction with heat shock protein (Hsp) 90 9,10 , a chaperone involved in the folding and stabilization of different molecules. Hsp90 has been shown to not only to protect from ubiquitin-dependent proteasomal degradation but has also been shown to maintain the proper conformation of PIM proteins 10 . The downstream targets of PIM1 signaling are typically regulated by direct phosphorylation by PIM1. Thus far, approximately 30 substrates have been shown to interact with and be phosphorylated by PIM1. Through phosphorylation of target proteins, PIM1 plays essential roles in the regulation of the cell cycle, cell proliferation, anti-apoptosis, multiple drug resistance, chromatin remodeling, protein translation, energy metabolism, and the stress response [11][12][13] . It has been suggested that PIM family members are weak oncogenes that can contribute to tumorigenesis by selectively enhancing tumorigenic properties 1,2 . However, PIM family members have also been shown to increase the capacity of other genes or chemical carcinogens to induce tumors [14][15][16] . The magnitude of the effect varies depending on...

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Differential Regulation of Androgen Receptor by PIM-1 Kinases via Phosphorylation-dependent Recruitment of Distinct Ubiquitin E3 Ligases

Cited by 53 publications

References 74 publications

ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer

ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer

Androgen receptor phosphorylation: biological context and functional consequences

The role of PIM1/PIM2 kinases in tumors of the male reproductive system

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