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Audrey Minden - One of the best experts on this subject based on the ideXlab platform.
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Decrypting the PAK4 transcriptome profile in mammary tumor forming cells using Next Generation Sequencing.
Genomics, 2017Co-Authors: Chetan K. Rane, William Senapedis, Erkan Baloglu, Misaal Patel, Li Cai, Audrey MindenAbstract:The p-21 Activated Kinase 4 (PAK4) protein kinase is implicated in many cancers, including breast cancer. Overexpression of PAK4 is sufficient to cause mouse mammary epithelial cells (iMMECs) to become tumorigenic. To gain insight into the long-term gene expression changes that occur downstream to PAK4, we performed Next Generation Sequencing of RNA collected from PAK4 overexpressing iMMECs and wild-type iMMECs. We identified a list of genes whose expression levels were altered in response to PAK4 overexpression in iMMECs. Some of these genes, including FoxC2 and ParvB, are consistent with a role for PAK4 in cancer. In addition, PAK4 regulates many genes that are frequently associated with the inflammatory response, raising the possibility that there is a connection between PAK4, inflammation, and the tumor microenvironment. This study delineates the PAK4 transcriptome profile in transformed mammary cells and can provide translational utility in other types of cancers as well.
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Pdx1-Cre-driven conditional gene depletion suggests PAK4 as dispensable for mouse pancreas development.
Scientific reports, 2017Co-Authors: Miao Zhao, Parisa Rabieifar, Tânia D. F. Costa, Ting Zhuang, Audrey Minden, Matthias Löhr, Rainer Heuchel, Staffan StrömbladAbstract:Constitutive depletion of p21-activated kinase 4 (PAK4) in the mouse causes embryonic lethality associated with heart and brain defects. Given that conventional gene depletion of PAK1 or PAK3 caused functional deficits in the mouse pancreas, while gene depletion of PAK5 or PAK6 did not, we asked if PAK4 might have a functional role in pancreas development. We therefore introduced conditional, Pdx1-Cre-mediated, pancreatic PAK4 gene depletion in the mouse, verified by loss of PAK4 protein expression in the pancreas. PAK4 knock-out (KO) mice were born at Mendelian ratios in both genders. Further, morphological and immunohistochemical examinations and quantifications indicated that exocrine, endocrine and ductal compartments retained the normal proportions and distributions upon PAK4 gene depletion. In addition, body weight records and a glucose tolerance test revealed no differences between WT and PAK4 KO mice. Together, this suggests that PAK4 is dispensable for mouse pancreas development. This will facilitate future use of our Pdx1-Cre-driven conditional PAK4 KO mouse model for testing in vivo potential functions of PAK4 in pancreatic disease models such as for pancreatitis and different pancreatic cancer forms.
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abstract 1864 in vivoefficacy of the PAK4 allosteric modulator kpt 9274 against a triple negative breast cancer model
Cancer Research, 2016Co-Authors: Chetan K. Rane, William Senapedis, Erkan Baloglu, Sharon Shacham, Audrey MindenAbstract:The p21-activated kinases (PAK) belong to a family of serine threonine kinases that promote cell survival and play an important role in cell proliferation, cell cycle regulation and cell shape determination. There are six mammalian PAK proteins which can be subdivided into two groups by sequence homology and mode of activation- Group A PAKs consisting of PAK 1, 2 and 3 and Group B PAKs consisting of PAK 4, 5 and 6. We have found that PAK4 protein levels are elevated in breast cancer, including Her2 positive and triple negative breast cancers, while it is expressed at low levels in normal mammary tissue, making it an attractive drug target. PAK inhibitors are being tested for effectiveness against solid tumors, but generation of highly specific PAK4 inhibitors has been a challenge. Furthermore, PAK4 has been reported to have kinase-independent functions. Therefore inhibiting its kinase activity alone might not be sufficient in blocking its tumorigenic potential. Our lab has previously reported the effectiveness of PAK4 allosteric modulators (PAM; KPT-8752 and KPT-9274) against multiple breast cancer cell lines. These novel PAK4 inhibitors reduce steady state protein levels and were able to block cell growth, cell migration and induce apoptosis in breast cancer cell lines, without affecting the control cells. Here, we tested the efficacy of the orally bioavailable PAM, KPT-9274 against tumors formed by the triple negative breast cancer cell line, MDA-MB-231. Following six weeks of treatment with orally administered KPT-9274 (150mg/kg bidx4), there was almost a five-fold reduction in tumor volume and tumor weight in the treatment group as compared to the control group. The treatment did not significantly affect mice body weight. After six weeks of treatment, the tumors were excised and analyzed for PAK4 levels. We observed a significant decrease in PAK4 levels in excised tumors from the treatment group as compared to those from the control group. PAK1 levels were monitored to see any off-target effects, but their levels were unchanged. Our results indicate that PAK4 plays a key functional role in triple negative breast cancer and treatment with an orally administered KPT-9274 was capable of specifically binding and inhibiting PAK4, and consequently reducing tumor growth. Future studies analyzing the effects of KPT-9274 in blocking PAK4 mediated functions that promote tumorigenesis are ongoing. Additional studies of the effectiveness of KPT-9274 on mammary fat pad tumors formed by MDA-MB-231 and the ER positive cell line, MCF7 are under investigation. Citation Format: Chetan Rane, William Senapedis, Erkan Baloglu, Sharon Shacham, Audrey G. Minden. In vivo efficacy of the PAK4 allosteric modulator KPT-9274 against a triple-negative breast cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1864.
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The PAK4 protein kinase in breast cancer.
ISRN oncology, 2012Co-Authors: Audrey MindenAbstract:Paks4, along with Paks5, and 6 are members of the group B family of p21-activated kinases (Paks). The Paks play multiple different roles in controlling cell morphology, cell growth, proliferation, and signaling. PAK4 has essential roles in embryonic development (Qu et al., 2003), but in adults high levels of PAK4 are frequently associated with cancer. PAK4 has been implicated in several types of cancer (Wells and Jones, 2010; Eswaran et al., 2009; Liu et al., 2008; and Liu et al., 2010) and it is strongly linked to breast cancer (Liu et al., 2008; Liu et al. 2010; Yu et al., 2009; Rafn et al., 2012; and So et al., 2012). Breast tumors and breast cancer cell lines frequently have high levels of PAK4 (Liu et al., 2008), and overexpression of PAK4 in mammary epithelial cells leads to tumorigenesis in mice (Liu et al., 2010). This paper summarizes the current work on the role of PAK4 in breast cancer.
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PAK4 6 in cancer and neuronal development
Cellular logistics, 2012Co-Authors: Audrey MindenAbstract:PAKs 4, 5 and 6 are members of the group B family of p21-activated kinases. Among this group, PAK4 has been most extensively studied. While it has essential roles in embryonic development, in adults high levels of PAK4 are frequently associated with cancer. PAK4 is overexpressed in a variety of cancers, and the PAK4 gene is amplified in some cancers. PAK4 overexpression is sufficient to cause oncogenic transformation in cells and in mouse models. The tight connection between PAK4 and cancer make it a promising diagnostic tool as well as a potential drug target. The group B PAKs also have important developmental functions. PAK4 is important for many early developmental processes, while PAK5 and PAK6 play roles in learning and memory in mice. This chapter provides an overview of the roles of the group B PAKs in cancer as well as development, and includes a discussion of PAK mediated signaling pathways and cellular functions.
Liu Cao - One of the best experts on this subject based on the ideXlab platform.
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oncogenic PAK4 regulates smad2 3 axis involving gastric tumorigenesis
Oncogene, 2014Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
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Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis
Oncogene, 2013Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
Chunyu Wang - One of the best experts on this subject based on the ideXlab platform.
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a mandatory role of nuclear PAK4 lifr axis in breast to bone metastasis of erα positive breast cancer cells
Oncogene, 2019Co-Authors: Hongyan Zhang, Yue Zhao, Chunyu Wang, Zhenguo Cheng, Lina Tang, Yunling Gao, Furong Liu, Nanxi Geng, Xue Rui, Yuee TengAbstract:The mechanism of estrogen receptor alpha (ERα)-positive breast cancer-associated bone metastasis is poorly understood. In this article, we report that nuclear p21-activated kinase 4 (nPAK4) is a novel repressor of ERα-mediated transactivation in a 17β-estradiol (E2)-dependent manner and promotes PAK4–ERα axis-mediated bone metastasis by targeting leukemia inhibitory factor receptor (LIFR) in ERα-positive breast cancer. An evaluation of clinical breast cancer samples revealed that nPAK4 is linked to ERα expression and appears to be associated with a poor prognosis in bone metastatic breast cancer. PAK4 bound and co-translocated with ERα from the cytoplasm to the nucleus upon stimulation with E2. nPAK4 enhanced the invasive potential of ERα-positive breast cancer cells in vitro and promoted breast cancer metastasis in vivo. Mechanistically, nPAK4 promoted the metastasis of ERα-positive breast cancer cells by targeting LIFR, a bone metastasis suppressor. Strikingly, the nuclear accumulation of PAK4 might promote aggressive phenotypes, highlighting nPAK4 as a novel predictive biomarker for ERα-positive breast cancer bone metastasis.
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oncogenic PAK4 regulates smad2 3 axis involving gastric tumorigenesis
Oncogene, 2014Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
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Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis
Oncogene, 2013Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
Hongyan Zhang - One of the best experts on this subject based on the ideXlab platform.
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a mandatory role of nuclear PAK4 lifr axis in breast to bone metastasis of erα positive breast cancer cells
Oncogene, 2019Co-Authors: Hongyan Zhang, Yue Zhao, Chunyu Wang, Zhenguo Cheng, Lina Tang, Yunling Gao, Furong Liu, Nanxi Geng, Xue Rui, Yuee TengAbstract:The mechanism of estrogen receptor alpha (ERα)-positive breast cancer-associated bone metastasis is poorly understood. In this article, we report that nuclear p21-activated kinase 4 (nPAK4) is a novel repressor of ERα-mediated transactivation in a 17β-estradiol (E2)-dependent manner and promotes PAK4–ERα axis-mediated bone metastasis by targeting leukemia inhibitory factor receptor (LIFR) in ERα-positive breast cancer. An evaluation of clinical breast cancer samples revealed that nPAK4 is linked to ERα expression and appears to be associated with a poor prognosis in bone metastatic breast cancer. PAK4 bound and co-translocated with ERα from the cytoplasm to the nucleus upon stimulation with E2. nPAK4 enhanced the invasive potential of ERα-positive breast cancer cells in vitro and promoted breast cancer metastasis in vivo. Mechanistically, nPAK4 promoted the metastasis of ERα-positive breast cancer cells by targeting LIFR, a bone metastasis suppressor. Strikingly, the nuclear accumulation of PAK4 might promote aggressive phenotypes, highlighting nPAK4 as a novel predictive biomarker for ERα-positive breast cancer bone metastasis.
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oncogenic PAK4 regulates smad2 3 axis involving gastric tumorigenesis
Oncogene, 2014Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
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Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis
Oncogene, 2013Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
Furong Liu - One of the best experts on this subject based on the ideXlab platform.
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a mandatory role of nuclear PAK4 lifr axis in breast to bone metastasis of erα positive breast cancer cells
Oncogene, 2019Co-Authors: Hongyan Zhang, Yue Zhao, Chunyu Wang, Zhenguo Cheng, Lina Tang, Yunling Gao, Furong Liu, Nanxi Geng, Xue Rui, Yuee TengAbstract:The mechanism of estrogen receptor alpha (ERα)-positive breast cancer-associated bone metastasis is poorly understood. In this article, we report that nuclear p21-activated kinase 4 (nPAK4) is a novel repressor of ERα-mediated transactivation in a 17β-estradiol (E2)-dependent manner and promotes PAK4–ERα axis-mediated bone metastasis by targeting leukemia inhibitory factor receptor (LIFR) in ERα-positive breast cancer. An evaluation of clinical breast cancer samples revealed that nPAK4 is linked to ERα expression and appears to be associated with a poor prognosis in bone metastatic breast cancer. PAK4 bound and co-translocated with ERα from the cytoplasm to the nucleus upon stimulation with E2. nPAK4 enhanced the invasive potential of ERα-positive breast cancer cells in vitro and promoted breast cancer metastasis in vivo. Mechanistically, nPAK4 promoted the metastasis of ERα-positive breast cancer cells by targeting LIFR, a bone metastasis suppressor. Strikingly, the nuclear accumulation of PAK4 might promote aggressive phenotypes, highlighting nPAK4 as a novel predictive biomarker for ERα-positive breast cancer bone metastasis.
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oncogenic PAK4 regulates smad2 3 axis involving gastric tumorigenesis
Oncogene, 2014Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
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Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis
Oncogene, 2013Co-Authors: Chunyu Wang, Hongyan Zhang, Zhenguo Cheng, Furong Liu, Dan Wang, Guanqiao Wang, Yufen Zhao, Liu CaoAbstract:The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin–proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.
