Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

Bristow, Jeanne M.; Reno, Theresa; Jo, Minji; Gonias, Steven L.; Klemke, Richard L.

doi:10.1074/jbc.m112.410910

Cited by 37 publications

(49 citation statements)

References 41 publications

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“…All of these proteins have been linked to critical cellular processes including cell migration, cytokinesis, proliferation, oncogenic transformation and membrane trafficking. These findings are consistant with previous work showing that PEAK1 associates with the actin cytoskeleton and localizes to focal adhesions where it plays a central role in cell migration, proliferation, and cancer metastasis (9, 10, 12–15). …”

Section: Resultssupporting

confidence: 89%

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

et al. 2017

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In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization and cell cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ co-immunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell-associated transcription factors (STF) including Oct4, Nanog, c-Myc and TEAD, thereby decreasing 3D tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity.

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Section: Resultssupporting

confidence: 89%

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

et al. 2017

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“…PEAK1 is a cytoskeleton-associated tyrosine kinase and scaffold protein that transmits growth factor and integrin adhesion signals from the cell's exterior, which is important for cell proliferation and migration [30-33, 45]. Our findings reported here demonstrate that PEAK1 is an important downstream mediator of eIF5A function in PDAC cell proliferation.…”

Section: Discussionmentioning

confidence: 55%

“…PEAK1 is a newly identified non-receptor tyrosine kinase that modulates Src kinase activity and plays an essential role in driving PDAC malignancy [30-33]. Like eIF5A, PEAK1 is amplified in PanINs and PDAC patient tissues in response to KRas activation [30].…”

Section: Resultsmentioning

confidence: 99%

“…We also demonstrate that pharmacological inhibition of eIF5A hypusination, or genetic knockdown of eIF5A proteins, inhibits PDAC cell growth in vitro and orthotopic tumor formation in vivo . Finally, we show that eIF5A proteins control the expression of the novel tyrosine kinase PEAK1 (pseudopodium-enriched atypical kinase 1; Sgk269), which we have previously shown is overexpressed in human PDAC tissues, and is critical for PDAC tumor growth, metastasis and gemcitabine resistance [30-33]. …”

Section: Introductionmentioning

confidence: 99%

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A Hypusine–eIF5A–PEAK1 Switch Regulates the Pathogenesis of Pancreatic Cancer

et al. 2014

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Deregulation of protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression. eIF5A1, and its highly related isoform eIF5A2, are translation initiation factors that have been implicated in a range of human malignancies, but how they control cancer development and disease progression is still poorly understood. Here, we investigated how eIF5A proteins regulate pancreatic ductal adenocarcinoma (PDAC) pathogenesis. eIF5A proteins are the only known proteins regulated by a distinct posttranslational modification termed hypusination, which is catalyzed by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The highly selective nature of the hypusine modification and its amenability to pharmacological inhibition make eIF5A proteins attractive therapeutic targets. We found that the expression and hypusination of eIF5A proteins are upregulated in human PDAC tissues and in premalignant pancreatic intraepithelial neoplasia (PanIN) tissues isolated from Pdx-1-Cre: LSL-KRASG12D mice. Knockdown of eIF5A proteins in PDAC cells inhibited their growth in vitro and orthotopic tumor growth in vivo, whereas amplification of eIF5A proteins increased PDAC cell growth and tumor formation in mice. Small molecule inhibitors of DHPS and DOHH both suppressed eIF5A hypusination, preventing PDAC cell growth. Interestingly, we found that eIF5A proteins regulate PDAC cell growth by modulating the expression of PEAK1, a non-receptor tyrosine kinase essential for PDAC cell growth and therapy resistance. Our findings suggest that eIF5A proteins utilize PEAK1 as a downstream effector to drive PDAC pathogenesis, and that pharmacological inhibition of the eIF5A-hypusine-PEAK1 axis may provide a novel therapeutic strategy to combat this deadly disease.

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“…Pinch1 may be required for granule polarization, as it is an obligate member of the IPP complex, and provides IPP protein stability (9). Sgk269 is a pseudo-kinase involved in the actin cytoskeleton and focal adhesion in migrating cells, via regulation of paxillin signaling (12, 13). Our analysis has identified a signaling network, centered around paxillin and ILK (Fig.…”

Section: Resultsmentioning

confidence: 99%

A signaling network stimulated by β ₂ integrin promotes the polarization of lytic granules in cytotoxic cells

et al. 2014

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Cytotoxic lymphocyte skill target cells by polarized release of the content of perforin-containing granules. In natural killer cells, the binding of β2 integrin to its ligand ICAM-1 is sufficient to promote not only adhesion but also lytic granule polarization. This provided a unique opportunity to study polarization in the absence of degranulation, and β2 integrin signaling independently of inside-out signals from other receptors. Using an unbiased proteomics approach we identified a signaling network centered on an integrin-linked kinase (ILK)–Pyk2–Paxillin core that was required for granule polarization. Downstream of ILK, the highly conserved Cdc42–Par6 signaling pathway that controls cell polarity was activated and required for granule polarization. These results delineate two connected signaling networks induced upon β2 integrin engagement alone, which are integrated to control polarization of the microtubule organizing center and associated lytic granules toward the site of contact with target cells during cellular cytotoxicity.

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Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

Cited by 37 publications

References 41 publications

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

A Hypusine–eIF5A–PEAK1 Switch Regulates the Pathogenesis of Pancreatic Cancer

A signaling network stimulated by β ₂ integrin promotes the polarization of lytic granules in cytotoxic cells

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Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

Cited by 37 publications

References 41 publications

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

A Hypusine–eIF5A–PEAK1 Switch Regulates the Pathogenesis of Pancreatic Cancer

A signaling network stimulated by β 2 integrin promotes the polarization of lytic granules in cytotoxic cells

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A signaling network stimulated by β ₂ integrin promotes the polarization of lytic granules in cytotoxic cells