Biology subjects

Thapa, N.

Publications and source records attributed to Thapa, N..

3 recordsLinked to original sources

bioRxiv2024

Enhanced PI3K/Akt Signaling in Response to p85α Loss is Regulated by Endosomal PI3Kα and PI3P

PI3K is a heterodimer of p110 catalytic subunit and p85 adaptor subunit that is activated by agonist-stimulated receptor tyrosine kinases. Although the interaction of p85 with activated receptors recruits p110 to membranes, studies have demonstrated that p85 loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. We recently demonstrated that p110 localizes to microtubules via MAP4, facilitating its interaction with activated receptor kinases in endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85 knock down the residual p110, coupled predominantly to p85{beta}, exhibits enhanced microtubule localization, MAP4 binding and interaction with endosomal receptor tyrosine kinases, thereby augmenting PI3K/Akt signaling. The interaction of the C2 domain of p110 with PI3P is required for recruiting p110 into endomembranes and enhancing PI3K/Akt signaling. These findings provide a mechanism for the augmented agonist-stimulated PI3K/Akt signaling upon p85 loss and point to novel therapeutic targets for cancer. IN BRIEFThis study provides the comprehensive mechanism for p85 loss induced and receptor tyrosine kinase stimulated PI3K/Akt signaling.

cell biology↗

bioRxiv2021

A p53-Phosphoinositide Signalosome Regulates Nuclear Akt Activation

The tumor suppressor p53 and the phosphoinositide 3-kinase (PI3K)-Akt pathway have fundamental roles in regulating cell growth, apoptosis and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear Akt activation by a p53-dependent mechanism that is independent from the canonical membrane-localized PI3K-Akt pathway. Upon genotoxic stress a nuclear p53-PI3,4,5P3 complex is generated in regions devoid of membranes by a nuclear PI3K, and this complex recruits all the kinases required to activate Akt and phosphorylate FOXOs, inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear Akt in an on/off fashion upon stress, whereas mutant p53 stimulates high basal Akt activity, indicating a fundamental difference. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, underscoring its therapeutic relevance. In briefp53 assembles a PI3K-Akt pathway that regulates nuclear Akt activation independent of the canonical pathway on membranes.

cell biology↗

bioRxiv2018

The Specificity of IQGAP1 Toward the PI3K-Akt Pathway is Dependent on the IQ3 motif

Epidermal growth factor receptor (EGFR) and its downstream phosphatidylinositol 3-kinase (PI3K) pathway are commonly deregulated in many cancers including head and neck cancer (HNC). Recently, we have shown that the IQ motif-containing GTPase-activating protein 1 (IQGAP1) provides a molecular platform to scaffold all the components from the PI3K-Akt pathway and results in the sequential generation of phosphatidylinositol-3,4,5-triphosphate (PI3,4,5P3). This makes the IQGAP1-PI3K scaffold a promising therapeutic target. In addition to the PI3K-Akt pathway, IQGAP1 also scaffolds the Ras-ERK pathway. To identify an IQGAP1 mutant that specifically loses IQGAP1-PI3K signaling but not other functions, we have focused on the IQ3 motif since this region binds with both the PIPK1 and PI3K enzymes and a short peptide derived from this sequence blocks binding and PI3K signaling. An IQ3 deletion mutant ({Delta}IQ3) in IQGAP1 was functionally compared with wild-type (WT) IQGAP1. We found that the IQ3 domain specifically mediates the PI3K-Akt pathway but does not regulate the Ras-ERK pathway. The IQ3 deletion mutant lost interactions with PI3K-Akt components but retained its binding of ERK pathway components and cell surface receptors, EGFR and integrins. In addition, the IQ3 deletion mutant lost regulation of cell migration. Consistently, the IQ3 motif derived peptide blocked Akt activation and led to the blockage of invasion mediated by EGFR organized into an integrin complex by syndecan-4. Taken together, this work has defined the IQGAP1 IQ3 motif as a specific target sequence for the scaffolding of the PI3K-AKT pathway.

cell biology↗