PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

Hsiao, Yu-Hsuan; Huang, Yu‐Ting; Hung, Chia-Yu; Kuo, Tzu-Chien; Luo, Fuh-Jinn; Yuan, Ta‐Chun

doi:10.1530/erc-16-0122

Cited by 15 publications

(16 citation statements)

References 53 publications

(46 reference statements)

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“…Pyk2 is a critical component of Ca 2+ -induced signaling pathways controlling cell survival in lung cancer ( 66 ), Src activation and metastasis in breast cancer ( 41 ), and in neuroprotection through the Pyk2/ERK/CREB pathway ( 84 ). The role of Pyk2 in the survival and proliferation of cancer cells is established ( 31 , 43 , 66 , 80 , 85 , 88 ). The work here confirms the importance of calcium influx through TRPM2 in activation of Pyk2 and modulation of cell viability in cancer ( 83 ).…”

Section: Discussionmentioning

confidence: 99%

“…Nonreceptor proline-rich tyrosine kinase 2 (Pyk2) is an important signaling molecule that senses changes in intracellular calcium levels and translates them into alterations in cell function. Pyk2 is overexpressed in many cancers ( 43 ) and Pyk2 inhibition attenuated survival and proliferation of small cell lung cancer ( 66 ), breast cancer ( 80 ), ovarian clear cell cancer ( 85 ), multiple myeloma ( 88 ), and prostate cancer ( 31 ). Ca 2+ influx through TRPM2 can activate Pyk2 and amplify ERK signaling in U937 cells.…”

Section: Introductionmentioning

confidence: 99%

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The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation

Hirschler-Laszkiewicz

Chen

Bao

et al. 2018

American Journal of Physiology-Cell Physiology

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Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential function in cell survival and is highly expressed in many cancers. Inhibition of TRPM2 in neuroblastoma by depletion with CRISPR technology or expression of dominant negative TRPM2-S has been shown to significantly reduce cell viability. Here, the role of proline-rich tyrosine kinase 2 (Pyk2) in TRPM2 modulation of neuroblastoma viability was explored. In TRPM2-depleted cells, phosphorylation and expression of Pyk2 and cAMP-responsive element-binding protein (CREB), a downstream target, were significantly reduced after application of the chemotherapeutic agent doxorubicin. Overexpression of wild-type Pyk2 rescued cell viability. Reduction of Pyk2 expression with shRNA decreased cell viability and CREB phosphorylation and expression, demonstrating Pyk2 modulates CREB activation. TRPM2 depletion impaired phosphorylation of Src, an activator of Pyk2, and this may be a mechanism to reduce Pyk2 phosphorylation. TRPM2 inhibition was previously demonstrated to decrease mitochondrial function. Here, CREB, Pyk2, and phosphorylated Src were reduced in mitochondria of TRPM2-depleted cells, consistent with their role in modulating expression and activation of mitochondrial proteins. Phosphorylated Src and phosphorylated and total CREB were reduced in TRPM2-depleted nuclei. Expression and function of mitochondrial calcium uniporter (MCU), a target of phosphorylated Pyk2 and CREB, were significantly reduced. Wild-type TRPM2 but not Ca2+-impermeable mutant E960D reconstituted phosphorylation and expression of Pyk2 and CREB in TRPM2-depleted cells exposed to doxorubicin. Results demonstrate that TRPM2 expression protects the viability of neuroblastoma through Src, Pyk2, CREB, and MCU activation, which play key roles in maintaining mitochondrial function and cellular bioenergetics.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation

Hirschler-Laszkiewicz

Chen

Bao

et al. 2018

American Journal of Physiology-Cell Physiology

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“…As another example, E2 signaling also occurs through the N-terminal truncated ERα isoform, or the orphan nuclear ER-related receptor α (ERRα) which is differentially expressed relative to ERα and ERβ in OBs and was reported to affect bone formation (Bonnelye and Aubin, 2002,Parikka et al, 2005,Bonnelye et al, 2001). In addition, a recent study found that Pyk2 promoted the expression and phosphorylation of the androgen receptor (Hsiao et al, 2016), suggesting a possible altered signaling of the androgen receptor in Pyk2-KO OBs.…”

Section: Discussionmentioning

confidence: 99%

Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene

Posritong

Hong

Eleniste

et al. 2018

Molecular and Cellular Endocrinology

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Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.

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“…For example, PYK2 modulates the signaling of androgen receptors and thus promotes growth of prostate cancer cells. 34 In breast cancer cells, PYK2 functions by integrating growth factor and cytokine receptors signaling. 35 Besides membrane receptors, PYK2 can also sustain endosomal-derived receptor signaling and enhance epithelial-to-mesenchymal transition of breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Significance of PYK2 level as a prognosis predictor in patients with colon adenocarcinoma after surgical resection

Liu¹,

Xu²

2018

OTT

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BackgroundProline-rich/Ca2+-activated tyrosine kinase 2 (PYK2) belongs to the non-receptor tyrosine kinase family, regulates downstream signaling via catalyzing protein phosphorylation. We aimed to investigate clinical significance and mechanisms of PYK2 in colon adenocarcinoma (CAC).MethodsReal time quantitative PCR and immunohistochemistry staining was used to evaluate the expression of PYK2 in clinical CAC tissues. Its association with clinicopathologic characteristics was analyzed by Chi-square test. Kaplan-Meier univariate survival analysis and multivariate Cox regression analysis were used to identify clinical significance of PYK2 in the overall survival of CAC patients. Transfection of PYK2 were conducted to reveal the underlying mechanism in regulating CAC progression.ResultsWe found that PYK2 was upregulated in CAC tissues compared with normal colon tissues on both RNA and protein levels. Higher tissue PYK2 expression level was closely associated with lymph node metastasis. Statistical analyses indicated PYK2 as an independent prognostic biomarker for CAC. Cellular studies demonstrated that PYK2 enhanced the capacities of tumor proliferation and invasion. Moreover, the phosphorylation level of AKT was positively correlated with PYK2 expression, subsequently modulate expression of c-Myc and Cyclin D1, suggesting that PYK2 may promote tumor progression through activating AKT signaling.ConclusionHigh PYK2 in CAC tissues indicate poor prognosis.

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PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells

Cited by 15 publications

References 53 publications

The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation

The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation

Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene

Significance of PYK2 level as a prognosis predictor in patients with colon adenocarcinoma after surgical resection

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