p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients

Siu, Michelle K.Y.; Chan, Hoi Yan; Kong, Daniel S; Wong, Eric T.T.; Wong, Oscar Gee‐Wan; Ngan, Hextan Y.S.; Tam, Kwok-kan; Zhang, Hongquan; Li, Zhilun; Chan, Queeny K.Y.; Tsao, Sai Wah; Strömblad, Staffan; Cheung, Annie N.Y.

doi:10.1073/pnas.0907481107

Cited by 162 publications

(245 citation statements)

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“…It has been described that PAK4 activities regulate cancer cell proliferation, migration, and invasion. Besides the abundance of PAK4, the phosphorylation of PAK4-Ser474 has been determined as a crucial factor in cancer progression (45). In this context, our research highlights a unique route how βAR-provoked cAMP fluxes might participate, besides PKA-mediated Erk1/2 modulation, in further diverse functions of the miscellaneous Rac-effectors PAKs.…”

Section: Discussionmentioning

confidence: 99%

“…physiological processes whereby PAK deregulation has been implicated in oncogenesis (26,44,45). It has been described that PAK4 activities regulate cancer cell proliferation, migration, and invasion.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, our research highlights a unique route how βAR-provoked cAMP fluxes might participate, besides PKA-mediated Erk1/2 modulation, in further diverse functions of the miscellaneous Rac-effectors PAKs. Given that PAKs activities are considered as marker for the prognosis of different types of cancer, we would like to note that besides PAKs abundance and its phosphorylation status, the GTP-Rac:PKA complex and βAR activities need to be considered (16,44,45,54). The disclosure of the involvement of the βAR-PKA cascade in regulation of Rac-PAK-mediated Erk1/2 activities offers an explanation how cAMP fluxes contribute to cell growth in a cell-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…It has been described that in an ovarian carcinoma mouse model, activation of the β2AR-PKA signaling axis contributes to tumor growth (24). In another study, it has been shown that PAK4 activities regulate ovarian cancer cell proliferation, migration, and invasion (45).…”

Section: Pka Rii Subunits Form Protein Complexes With Rac1 In Vitro Amentioning

confidence: 99%

“…Therefore, we decided to analyze one human ovarian cancer cell line (OVCAR3) from this study (45) for the involvement of βAR-PKA and PAK4/6 signaling in Erk1/2 activation and proliferation. First, we demonstrate basal levels of PAK4-Ser474 and PAK6-Ser560 phosphorylation in OVCAR3 cells.…”

Section: Pka Rii Subunits Form Protein Complexes With Rac1 In Vitro Amentioning

confidence: 99%

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Reciprocal regulation of PKA and Rac signaling

Bachmann

Riml

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac-bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTPRac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA-boosted activation of Raf-Mek-Erk. Consequently GTPRac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac-mediated activation of nuclear Erk1/2 signaling. signal transduction | cross-talk S ignal transduction cascades coordinate the plethora of extracellular stimuli into biological responses within cells. The specificity of receptor-initiated signaling responses is encoded by spatial and temporal dynamics of downstream signaling networks (1). These networks, initiating from e.g., the G protein-coupled receptor (GPCR) superfamily and receptor tyrosine kinases (RTK), tightly regulate signaling pathways at several critical points via feedback loops and cross-talk among other pathways (2-5). A large number of GPCR signaling cascades uses cAMP as an intracellular second messenger (3, 6). In response to hormone binding to distinct GPCRs, cAMP is produced and binds to its canonical effector, the cAMP-dependent protein kinase A (PKA). cAMP binding to the PKA regulatory subunits (R) induces dissociation of the tetrameric PKA holoenzyme, resulting in active PKA catalytic subunits (PKAc; Fig. 1C) (7, 8). To ensure substrate specificity, PKA is tethered to distinct subcellular compartments through physical interaction with A-kinase anchoring proteins (AKAPs; refs. 9 and 10). It has been long regarded that the...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pka Rii Subunits Form Protein Complexes With Rac1 In Vitro Amentioning

confidence: 99%

Section: Pka Rii Subunits Form Protein Complexes With Rac1 In Vitro Amentioning

confidence: 99%

See 3 more Smart Citations

Reciprocal regulation of PKA and Rac signaling

Bachmann

Riml

Huber

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer

Wang

Zhang

et al. 2013

The Anatomical Record

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The p21-activated kinases have been implicated in the control of cell cycle progression. However, the biological mechanism underlying the role of p21-activated kinase 4 (PAK4) in cell cycle control remains unknown. Here, by using quantitative RT-PCR and immunoblot analyses, we discovered that over-expression of PAK4 could suppress cyclin-dependent kinase inhibitor 1C ( p57 Kip2 ) expression in the MCF-7 human breast cancer cell line, whereas lentiviral vector-mediated small interfering RNA (siRNA) knockdown of PAK4 markedly promoted p57Kip2 expression in MCF-7 cells. Furthermore, PAK4-mediated down-regulation of p57Kip2 was reversed by MG132, a specific proteasome inhibitor. The ubiquitination assay confirmed that the activity of PAK4 attenuated p57Kip2 protein stability through the ubiquitin-proteasome pathway in MCF-7 cells. Moreover, a significant inverse correlation between PAK4 and p57Kip2 protein levels was observed in breast cancer tissues by immunohistochemical analysis. Taken together, our data demonstrate a novel function for PAK4 in regulating the stability of p57 Kip2, possibly through the ubiquitin-proteasome pathway, leading to increased proliferation of breast cancer cells. Thus, PAK4 may be used as a potential diagnostic and therapeutic target for human breast cancer. Anat Rec, 296:1561Rec, 296: -1567Rec, 296: , 2013. V C 2013 Wiley Periodicals, Inc.

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MiR‐145 inhibits human colorectal cancer cell migration and invasion via PAK4‐dependent pathway

et al. 2017

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MicroRNA-145 (miR-145), as a tumor-suppressive miRNA, has been demonstrated down-regulated in colorectal cancer (CRC) cells, and could inhibit CRC cells growth. However, the molecular pathway in which miR-145 modulates CRC malignant transformation has not been fully revealed. Here, we reported an intense correlation between the expressions of PAK4 and miR-145 in human CRC cell lines. Transwell assay verified overexpression of miR-145, as well as knockdown of PAK4, significantly suppressed cell migration and invasion ability. The impaired migration and invasion ability of SW1116 cells was affected through the down-regulation of phosphorylation level of LIMK1 and cofilin in a PAK4-dependent manner. Collectively, we have demonstrated that miR-145 suppressed CRC migration and invasion through PAK4 pathway, which provides an attractive microRNA-based therapeutic target for CRC. Cancer Medicine Open Access 1332

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p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients

Cited by 162 publications

References 36 publications

Reciprocal regulation of PKA and Rac signaling

Reciprocal regulation of PKA and Rac signaling

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer

MiR‐145 inhibits human colorectal cancer cell migration and invasion via PAK4‐dependent pathway

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p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients

Cited by 162 publications

References 36 publications

Reciprocal regulation of PKA and Rac signaling

Reciprocal regulation of PKA and Rac signaling

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57Kip2 in Human Breast Cancer

MiR‐145 inhibits human colorectal cancer cell migration and invasion via PAK4‐dependent pathway

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P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer