Quantitative phosphoproteomics reveals the protein tyrosine kinase Pyk2 as a central effector of olfactory receptor signaling in prostate cancer cells

Wiese, Heike; Gelis, Lian; Wiese, Sebastian; Reichenbach, Christa; Jovancevic, Nikolina; Osterloh, Markus; Meyer, Helmut E.; Neuhaus, Eva M.; Hatt, Hanns; Radziwill, Gerald; Warscheid, Bettina

doi:10.1016/j.bbapap.2014.09.002

Cited by 29 publications

(40 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Strong cation exchange chromatography and titanium dioxide enrichment were essentially performed as described7576. In brief, 30 fractions a 2.1 ml were collected throughout the strong cation exchange chromatography gradient.…”

Section: Methodsmentioning

confidence: 99%

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

et al. 2016

Self Cite

View full text Add to dashboard Cite

Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.

show abstract

Section: Methodsmentioning

confidence: 99%

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this context, OR51E2 was the first identified hormone-sensitive membrane receptor involved in the growth mechanisms of PCa cells [45]. The β-ionone-dependent activation of OR51E2 resulted in a reduced proliferation of PCa cells via the Src-Pyk2- p38MAPK signaling pathway [45, 47, 48]. Controversy studies demonstrated prostate cancer growth promoting function of PSGR in vivo [49, 50].…”

Section: Introductionmentioning

confidence: 99%

The activation of OR51E1 causes growth suppression of human prostate cancer cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor (AR). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) OR51E1 [prostate-specific G-protein coupled receptor 2 (PSGR2)] and OR51E2 (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The OR51E1 agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated AR target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced E2F1 mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the OR2AG1 agonist amyl butyrate, neither of which activates OR51E1, did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another OR51E1 agonist, also induces cellular senescence. Thus, our results suggest the involvement of OR51E1 in growth processes of PCa cells and its impact on AR-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.

show abstract

“…There are fourteen identified phosphorylation events by seven different protein kinases (2, 3, 13). The specific amino acids phosphorylated by Nck-interacting kinase (NIK) and RhoA Kinase (Rock) have not been identified.…”

Section: Introductionmentioning

confidence: 99%

RhoA Kinase (Rock) and p90 Ribosomal S6 Kinase (p90Rsk) phosphorylation of the sodium hydrogen exchanger (NHE1) is required for lysophosphatidic acid-induced transport, cytoskeletal organization and migration

Wallert

Hammes

Nguyen

et al. 2015

Cellular Signalling

View full text Add to dashboard Cite

The sodium hydrogen exchanger isoform one (NHE1) plays a critical role coordinating asymmetric events at the leading edge of migrating cells and is regulated by a number of phosphorylation events influencing both the ion transport and cytoskeletal anchoring required for directed migration. Lysophosphatidic acid (LPA) activation of RhoA kinase (Rock) and the Ras-ERK growth factor pathway induces cytoskeletal reorganization, activates NHE1 and induces an increase in cell motility. We report that both Rock I and II stoichiometrically phosphorylate NHE1 at threonine 653 in vitro using mass spectrometry and reconstituted kinase assays. In fibroblasts expressing NHE1 alanine mutants for either Rock (T653A) or ribosomal S6 kinase (Rsk; S703A) we show each site is partially responsible for the LPA-induced increase in transport activity while NHE1 phosphorylation by either Rock or Rsk at their respective site is sufficient for LPA stimulated stress fiber formation and migration. Furthermore, mutation of either T653 or S703 leads to a higher basal pH level and a significantly higher proliferation rate. Our results identify the direct phosphorylation of NHE1 by Rock and suggest that both RhoA and Ras pathways mediate NHE1-dependent ion transport and migration in fibroblasts.

show abstract

Quantitative phosphoproteomics reveals the protein tyrosine kinase Pyk2 as a central effector of olfactory receptor signaling in prostate cancer cells

Cited by 29 publications

References 41 publications

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

A systems study reveals concurrent activation of AMPK and mTOR by amino acids

The activation of OR51E1 causes growth suppression of human prostate cancer cells

RhoA Kinase (Rock) and p90 Ribosomal S6 Kinase (p90Rsk) phosphorylation of the sodium hydrogen exchanger (NHE1) is required for lysophosphatidic acid-induced transport, cytoskeletal organization and migration

Contact Info

Product

Resources

About