Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK

Clayton, Natasha S; Fox, Millie; Vicente-Garcia, Jose Julio; Schroeder, Courtney M.; Littlewood, Trevor D.; Wilde, Jonathon I; Krishnan, Kadalmani; Brown, Murray J. B.; Crafter, Claire; Mott, Helen R.; Owen, Darerca

doi:10.1016/j.jbc.2022.101916

Cited by 10 publications

(13 citation statements)

References 46 publications

(75 reference statements)

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“…Based on the activation mode, it is divided into the 1A and 1B categories (Sun and Meng, 2020;Yue et al, 2021). Class 1A PI3K is activated by many cell-surface tyrosine kinases and consists of catalytic p110 and regulated p85 subunits (Clayton et al, 2022). Class II and III PI3Ks are necessary to maintain normal cell functions, up to now, Both are not yet shown to have carcinogenic effects in human (Bilanges et al, 2019).…”

Section: Pi3k/akt/mammalian Target Of Rapamycin Signal Pathwaymentioning

confidence: 99%

Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma

Wei

et al. 2022

Front. Mol. Neurosci.

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As is known to all, glioma, a global difficult problem, has a high malignant degree, high recurrence rate and poor prognosis. We analyzed and summarized signal pathway of the Hippo/YAP, PI3K/AKT/mTOR, miRNA, WNT/β-catenin, Notch, Hedgehog, TGF-β, TCS/mTORC1 signal pathway, JAK/STAT signal pathway, MAPK signaling pathway, the relationship between BBB and signal pathways and the mechanism of key enzymes in glioma. It is concluded that Yap1 inhibitor may become an effective target for the treatment of glioma in the near future through efforts of generation after generation. Inhibiting PI3K/Akt/mTOR, Shh, Wnt/β-Catenin, and HIF-1α can reduce the migration ability and drug resistance of tumor cells to improve the prognosis of glioma. The analysis shows that Notch1 and Sox2 have a positive feedback regulation mechanism, and Notch4 predicts the malignant degree of glioma. In this way, notch cannot only be treated for glioma stem cells in clinic, but also be used as an evaluation index to evaluate the prognosis, and provide an exploratory attempt for the direction of glioma treatment. MiRNA plays an important role in diagnosis, and in the treatment of glioma, VPS25, KCNQ1OT1, KB-1460A1.5, and CKAP4 are promising prognostic indicators and a potential therapeutic targets for glioma, meanwhile, Rheb is also a potent activator of Signaling cross-talk etc. It is believed that these studies will help us to have a deeper understanding of glioma, so that we will find new and better treatment schemes to gradually conquer the problem of glioma.

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Section: Pi3k/akt/mammalian Target Of Rapamycin Signal Pathwaymentioning

confidence: 99%

Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma

Wei

et al. 2022

Front. Mol. Neurosci.

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“…Instead, research efforts have focussed on the hyperactivated STAT activators as tractable targets. A previous yeast-2-hybrid screen in our lab (Clayton et al, 2022) identified STAT3 as a potential ACK interacting partner, a relationship that has been reported in the literature (Mahendrarajah et al, 2017).…”

Section: Introductionmentioning

confidence: 59%

The Cdc42 effector and non-receptor tyrosine kinase, ACK defines a distinct STAT5 transcription signature in a chronic myeloid leukaemia cell model

Corry

Jachimowicz

Keith

et al. 2022

Preprint

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Activated Cdc42-associated kinase (ACK) is a Rho family effector that is widely implicated in cancer. Here, we describe new roles for ACK in transcriptional regulation mediated by its relationship with the signal transducer and activators of transcription (STAT) family. We show that ACK can interact with STAT3, STAT5A and STAT5B, and augments phosphorylation at the conserved activation tyrosine on these STAT members. ACK stimulates oncogenic STAT nuclear relocation and transcriptional activation. We also identify endogenous relationships between ACK and STAT family members in haematopoietic disease cell lines. In the K562 chronic myeloid leukaemia cell line, we confirm that ACK contributes to the pool of active, nuclear STAT5. By interrogating ACK knock out cells we describe an ACK-driven STAT5 transcriptional signature in K562s. We propose ACK as a contributor to hyperactivated STAT5 signalling in this CML cell line and reveal a new route for therapeutic intervention.

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“…Activated Cdc42 leads to actin polymerization into lopodia, and the downstream effectors of Cdc42 and ACK are also activated. Studies have identi ed class 1A PI3K (PI3Ks) as a novel ACK1 binding partner that is critical for PDGF-dependent actin rearrangement, indicating that ACK1 may also participate in actin arrangement [45][46][47] . Additionally, ACK1 can directly bind and phosphorylate the Arp2/3 regulatory protein cortactin, contributing to ligand-mediated EGFR internalization [48] .…”

Section: Discussionmentioning

confidence: 99%

Myristoylated alanine rich C kinase substrate/Activated Cdc42-associated kinase 1 regulates cortactin to promote neutrophil elastase-induced mucin secretion in airway epithelial cells

Zhong

Perelman

et al. 2022

Preprint

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Purpose Mucus secretion is excessively increased in airway epithelial cells in pathological states. This process is related to the cytoskeleton and the increase in exocytosis sites, but the movement of secreted molecules and how secretion increases remain unclear. In this study, we examined the potential role of myristoylated alanine rich C kinase substrate (MARCKS) and the cortical actin-binding protein cortactin in airway mucin secretion. Also we investigated the effect of activated Cdc42-associated kinase 1 (ACK1) in this process. Methods Human airway epithelial cells were treated with neutrophil elastase (NE) after treatment with siRNA to specifically knock down MARCKS, ACK1 and cortactin expression. The expression and localization of cortactin and MARCKS were observed by western blotting and immunofluorescence, and the phosphorylated forms of MARCKS, cortactin and ACK1 were detected. The interaction of cortactin and ACK1 was analyzed by coimmunoprecipitation. MUC5AC protein expression was measured by ELISAs. Results Phosphorylated cortactin was highly expressed, mainly at the cell membrane, after NE stimulation, and phosphorylated MARCKS was mainly expressed in the cytoplasm. Coimmunoprecipitation revealed that ACK1 and cortactin interacted with each other. Knockdown of MARCKS suppressed phosphorylation of cortactin, while cortactin siRNA had no significant effect on MARCKS activation. Knockdown of MARCKS, cortactin and ACK1 by siRNA attenuated the phosphorylation of cortactin and reduced MUC5AC secretion. Conclusion These results suggest that both cortactin and MARCKS are involved in MUC5AC secretion by increasing F-actin polymerization and translocation and that MARCKs and ACK1 play an important role in the activation of cortactin.

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Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK

Cited by 10 publications

References 46 publications

Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma

Research Progress on the Regulation Mechanism of Key Signal Pathways Affecting the Prognosis of Glioma

The Cdc42 effector and non-receptor tyrosine kinase, ACK defines a distinct STAT5 transcription signature in a chronic myeloid leukaemia cell model

Myristoylated alanine rich C kinase substrate/Activated Cdc42-associated kinase 1 regulates cortactin to promote neutrophil elastase-induced mucin secretion in airway epithelial cells

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