The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1)

Kim, Yong Bae; Shin, Yong Jae; Roy, Adhiraj; Kim, Jeong-Ho

doi:10.1074/jbc.m115.675124

Cited by 22 publications

(16 citation statements)

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“…Finally, we assessed whether PAKs may be activated by noradrenaline, endothelins, or dihydrotestosterone in WPMY-1 cells. Activation of group I PAKs includes phosphorylation at common positions, which may be investigated using phospho-specific antibodies [ 35 – 37 ]. Stimulation of WPMY-1 cells with endothelin-1 (3 μM) for 10 or 20 min increased the content of phosphorylated group I PAKs (i. e., PAK1-3), while the content of PAK1 and β-actin was similar in stimulated and control cells ( Fig 8 ).…”

Section: Resultsmentioning

confidence: 99%

“…Our findings with PAK inhibitors in WPMY-1 cells are in line with previous observations. Thus, a critical role of PAKs for actin organization, including polymerization and its organization to filaments, as well as a role for actin-dependent functions such as migration, morphology, proliferation, or contraction was observed in various cell types [ 35 , 44 – 47 , 72 ]. Deorganization of actin filaments, going along with depolymerization, shortening of filaments, and alterations in morphology can be seen in our phalloidin stainings of WPMY-1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of PAK1-3 involves autophosphorylation at threonine 402 or corresponding sites (threonine 423), which may be assessed using site- and phospho-specific antibodies [ 8 , 35 – 37 ]. For assessments of agonist-induced PAK phosphorylation, WPMY-1 cells were grown in T75 flasks.…”

Section: Methodsmentioning

confidence: 99%

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P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

et al. 2016

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Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

et al. 2016

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“…This is the first report of p41ARC serving as a downstream effector of PAK1 signaling in skeletal muscle cells. PAK1 has been shown to phosphorylate p41ARC in vitro, in MCF-7 cancer cells upon EGF stimulation (24,26), and in melanoma cells (25). p41ARC is one of two principle ARP2/3 subunits, the other and more commonly used subunit being ARPC1A (40).…”

Section: Cytoskeletal Regulation Of Skeletal Muscle Glucose Uptakementioning

confidence: 99%

The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)–mediated glucose uptake into skeletal muscle cells

Tunduguru

Zhang

Aslamy

et al. 2017

Journal of Biological Chemistry

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Defects in translocation of the glucose transporter GLUT4 are associated with peripheral insulin resistance, preclinical diabetes, and progression to type 2 diabetes. GLUT4 recruitment to the plasma membrane of skeletal muscle cells requires F-actin remodeling. Insulin signaling in muscle requires p21-activated kinase-1 (PAK1), whose downstream signaling triggers actin remodeling, which promotes GLUT4 vesicle translocation and glucose uptake into skeletal muscle cells. Actin remodeling is a cyclic process, and although PAK1 is known to initiate changes to the cortical actin-binding protein cofilin to stimulate the depolymerizing arm of the cycle, how PAK1 might trigger the polymerizing arm of the cycle remains unresolved. Toward this, we investigated whether PAK1 contributes to the mechanisms involving the actin-binding and -polymerizing proteins neural Wiskott-Aldrich syndrome protein (N-WASP), cortactin, and ARP2/3 subunits. We found that the actin-polymerizing ARP2/3 subunit p41ARC is a PAK1 substrate in skeletal muscle cells. Moreover, co-immunoprecipitation experiments revealed that insulin stimulates p41ARC phosphorylation and increases its association with N-WASP coordinately with the associations of N-WASP with cortactin and actin. Importantly, all of these associations were ablated by the PAK inhibitor IPA3, suggesting that PAK1 activation lies upstream of these actin-polymerizing complexes. Using the N-WASP inhibitor wiskostatin, we further demonstrated that N-WASP is required for localized F-actin polymerization, GLUT4 vesicle translocation, and glucose uptake. These results expand the model of insulin-stimulated glucose uptake in skeletal muscle cells by implicating p41ARC as a new component of the insulin-signaling cascade and connecting PAK1 signaling to N-WASP-cortactin-mediated actin polymerization and GLUT4 vesicle translocation.

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“…25 It was reported that CKIP-1 negatively regulates several important pathways, such as the transforming growth factorb/bone morphogenetic protein, Wnt/ b-catenin and PI3K/protein kinase B signalling pathways. 16,[26][27][28] However it is not clear whether CKIP-1 is related to the Ras/ERK signalling pathway. To clarify this, the current study measured the protein levels of Ras and ERK1/2 in CKIP-1 shRNA and overexpressed SGC7901 cells.…”

Section: Discussionmentioning

confidence: 99%

High expression of the CKIP-1 gene might promote apoptosis through downregulation of the Ras/ERK signalling pathway in the intestinal type of gastric cancer

Cao

et al. 2020

J Int Med Res

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Objective: To investigate the effect of the casein kinase 2 interacting protein 1 (CKIP-1) on the apoptosis of the intestinal type of gastric cancer (GC). Methods: The levels of CKIP-1 protein and the rates of apoptosis were measured in tissue samples of the intestinal type of GC and human GC cell lines. The rate of apoptosis and the protein levels of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), cleaved cysteinyl aspartate specific protease 3 (cleaved caspase-3), cleaved caspase-9, rat sarcoma (Ras), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) were analysed in SGC7901 cells expressing CKIP-1 short hairpin RNA (shRNA; knockdown) and SGC7901 cells overexpressing CKIP-1. Results: The levels of CKIP-1 protein were significantly lower in the intestinal type of GC tissues compared with the samples of intestinal metaplasia. Both the levels of CKIP-1 protein and the levels of apoptosis decreased gradually with decreasing cell differentiation in the intestinal type of GC tissue and cell lines; and they were positively correlated. In the CKIP-1 shRNA group, the rate of apoptosis and the levels of Bax, cleaved caspase-3 and cleaved caspase-9 were decreased; and the levels of Bcl-2, Ras and the ratio of p-ERK/ERK were increased, compared with the control group. Opposite results were observed in the CKIP-1 overexpression group.

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The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1)

Cited by 22 publications

References 50 publications

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)–mediated glucose uptake into skeletal muscle cells

High expression of the CKIP-1 gene might promote apoptosis through downregulation of the Ras/ERK signalling pathway in the intestinal type of gastric cancer

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