Role of p-21-Activated Kinases in Cancer Progression

King, H. W.; Nicholas, Nicole S.; Wells, Claire M.

doi:10.1016/b978-0-12-800255-1.00007-7

Cited by 89 publications

(97 citation statements)

References 214 publications

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“…Dephosphorylation of PREX1 with either -phosphatase or PP1␣ increases GEF activity, and PKAmediated phosphorylation of PREX1 reduces both the binding of PREX1 to G␤␥ and G␤␥-dependent activation of PREX1 GEF activity (30 -32). By performing PIP 3 pulldowns in MCF7 cells, we found that treatment with neuregulin, insulin, or IGF1 for 30 min reduced the total amount of PREX1 that bound to PIP 3 (Fig. 3A).…”

Section: Prex1 Is Phosphorylated Through a Pi3k-dependent Mechanism Dmentioning

confidence: 99%

“…We have shown previously that insulin-mediated phosphorylation of PREX2 reduces binding to PIP 3 to prevent PIP 3 -dependent activation of GEF activity (33). Furthermore, multiple studies on PREX1 have shown that phosphorylation can affect GEF activity.…”

Section: Prex1 Is Phosphorylated Through a Pi3k-dependent Mechanism Dmentioning

confidence: 99%

“…Phosphorylation of PREX1 Reduces PIP 3 Binding and PIP 3 -mediated GEF Activation-We then sought to determine the functional consequences of RTK-dependent phosphorylation of PREX1. We have shown previously that insulin-mediated phosphorylation of PREX2 reduces binding to PIP 3 to prevent PIP 3 -dependent activation of GEF activity (33).…”

Section: Prex1 Is Phosphorylated Through a Pi3k-dependent Mechanism Dmentioning

confidence: 99%

“…PAK-dependent phosphorylation of PREX2, which occurs downstream of Rac activation, reduces PIP 3 and G␤␥ binding as well as PIP 3 and G␤␥-stimulated PREX2 GEF activity, suggesting that these phosphorylation events are part of a negative feedback circuit to reduce Rac activation after insulin stimulation (33). In this study, we found that PREX1 is phosphorylated after insulin treatment of breast cancer cells and that insulin, neuregulin, and IGF1-mediated phosphorylation of PREX1 are PI3K-and PAK-dependent.…”

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confidence: 99%

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PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

Barrows

Parsons

2016

Journal of Biological Chemistry

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Section: Prex1 Is Phosphorylated Through a Pi3k-dependent Mechanism Dmentioning

confidence: 99%

Section: Prex1 Is Phosphorylated Through a Pi3k-dependent Mechanism Dmentioning

confidence: 99%

Section: Prex1 Is Phosphorylated Through a Pi3k-dependent Mechanism Dmentioning

confidence: 99%

mentioning

confidence: 99%

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PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

Barrows

Parsons

2016

Journal of Biological Chemistry

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“…1,2 The PAK family comprises two subgroups based on sequence homology: group I (PAKs 1−3) and group II (PAKs 4−6). Group I PAKs have high sequence identity in the kinase domain and possess an autoinhibitory domain, which is relieved by binding of the GTP-binding proteins Rac or Cdc42, while group II PAKs have lower kinase domain homology and are not activated by Rho GTPases.…”

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confidence: 99%

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

McCoull

Hennessy

Blades

et al. 2016

ACS Med. Chem. Lett.

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Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structurebased drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology. KEYWORDS: PAK, LLE, kinase selectivity, probe, bis-anilino pyrimidine T he p21-activated kinases (PAKs) are a family of six serine/ threonine-specific intracellular protein kinases that are positioned at the intersection of multiple signaling pathways of importance in cancer progression. 1,2 The PAK family comprises two subgroups based on sequence homology: group I (PAKs 1−3) and group II (PAKs 4−6). Group I PAKs have high sequence identity in the kinase domain and possess an autoinhibitory domain, which is relieved by binding of the GTP-binding proteins Rac or Cdc42, while group II PAKs have lower kinase domain homology and are not activated by Rho GTPases. 3 Group I PAKs are overexpressed in a wide variety of cancers, and PAK1 is commonly overexpressed in breast tumors with poor prognosis. 4 In ovarian cancer cells characterized by PAK1 amplification, treatment with a PAK1 inhibitor decreased proliferation and migration. 5 In tumors characterized by neurofibromatosis type 2 (NF2) inactivation, group I PAKs have been shown to be hyperactivated. 6 Consequently, there is increasing interest in identifying potent and selective small molecule inhibitors of PAK1 for therapeutic use in tumors characterized by PAK activation. 7 There are relatively few chemotypes described in the literature for PAK1 inhibitors 8 and only pan-PAK inhibitor PF-3578309 9 progressed into clinical trials but is now stopped. Ourselves 10 and others 11,12 have recently disclosed PAK1 inhibitors but achieving high kinase selectivity with a chemotype amenable to achieving oral exposure has been challenging. Without high kinase selectivity it is difficult to discern whether PAK1 is driving efficacy; thus, new alternative chemotypes for selective PAK1 inhibition are required.Following a kinase-focused subset screen (120k compounds) of the AstraZeneca compound collection, bis-anilino pyrimidine 1 (Figure 1) was identified as a modestly potent PAK1 inhibitor (IC 50 = 100 nM) with 11-fold selectivity over PAK4 (Table 1).While selectivity within the group I PAKs was not expected, PAK4 was utilized to monitor selectivity against group II PAKs. Selectivity against some key kinase antitargets, KDR and FGFR1, 13 was modest. Since 1 originated from an EphB4 kinase project, 14 a member of the Src kinase family, high activity for Src kinase was expected. Src family kinase activity was of less concern to us but was monitored as a measure of overall kinase selectivity. A crystal structure of 1 bound...

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Effects of PAK4/LIMK1/Cofilin‐1 signaling pathway on proliferation, invasion, and migration of human osteosarcoma cells

Yao

Zhao

et al. 2020

Clinical Laboratory Analysis

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Purpose To explore the effects of PAK4/LIMK1/Cofilin‐1 signaling pathway on the proliferation, invasion, and migration of human osteosarcoma cells. Methods The expression of PAK4/LIMK1/Cofilin‐1 was detected by immunohistochemistry in osteosarcoma tissues. The osteosarcoma cell line MG63 was transfected and divided into Mock, Control siRNA, si‐PAK4, LIMK1, and si‐PAK4+LIMK1 groups. Then, the cellular biological features of MG63 cells were detected by CCK‐8, wound‐healing, Transwell, and flow cytometry methods. The relationship of PAK4 and LIMK1 was performed by co‐immunoprecipitation test, and the protein expression of PAK4/LIMK1/Cofilin‐1 was determined by Western blotting. Finally, the effect of PAK4 on the growth of osteosarcoma was verified by subcutaneous transplantation model of osteosarcoma in nude mice. Results The expression of PAK4/LIMK1/Cofilin‐1 in both osteosarcoma tissues and cells was up‐regulated. Positive PAK4, LIMK1, and Cofilin‐1 expressions in osteosarcoma were associated with the clinical stage, distant metastasis, and tumor grade. The MG63 cell viability, migration, and invasion, as well as the expression of PAK4, p‐LIMK/LIMK, and p‐Cofilin‐1/Cofilin‐1, were restrained by the knock down of PAK4 while it promoted apoptosis. PAK4 silencing also suppressed the growth of subcutaneous transplanted tumor in nude mice. Co‐immunocoprecipitation showed that LIMK and PAK4 protein can form complex in osteosarcoma cells. Besides, LIMK1 overexpression reversed the inhibition effect of PAK4 siRNA on the growth of osteosarcoma cells. Conclusion The expression of PAK4/LIMK1/Cofilin‐1 pathway in osteosarcoma tissues was up‐regulated. Thus, PAK4 inhibition may restrict the osteosarcoma cell proliferation, invasion, and migration but promote its apoptosis via decreasing the activity of LIMK1/Cofilin‐1 pathway.

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Role of p-21-Activated Kinases in Cancer Progression

Cited by 89 publications

References 214 publications

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

Effects of PAK4/LIMK1/Cofilin‐1 signaling pathway on proliferation, invasion, and migration of human osteosarcoma cells

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