Browsing by Author "Sulaiman, Mahnoor"

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    Class IA PI3K isoforms lead to differential signalling downstream of PKB/Akt
    (Walter De Gruyter GMBH, 2023-12-20) Çatalak Yılmaz, Hazal Beril; Sulaiman, Mahnoor; Işık, Özlem Aybüke; Çizmecioğlu, Onur
    Objectives The catalytic subunits of Class IA PI3K, p110 alpha, p110 beta, and p110 delta, phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the plasma membrane. In cancer, these catalytic subunits are usually found to be altered or amplified. Because pan-PI3K inhibition results in systemic toxicities, finding specific targets for the ubiquitous PI3K isoforms offers considerable potential for enhancing the effectiveness of PI3K-targeted therapy. Methods We aim to delineate the isoform-specific druggable targets of the PI3K by deleting PIK3CA (encoding p110 alpha) and PIK3CB (encoding p110 beta) by Cre mediated excision and ectopically expressing p110 alpha, p110 beta, or p110 delta with or without myristoylation (Myr) tag in mouse embryonic fibroblasts (MEFs). Myr is a lipidation signal that translocates proteins to plasma membrane permanently. This translocation renders p110s constitutively activated as they remain in close proximity to PIP(2 )on the membrane. Results Unique and redundant Akt targets are identified downstream of different PI3K isoforms. mTORC1, one of the targets of fully-activated Akt, has been observed to be differentially regulated in MEFs upon expression of p110 alpha or p110 beta. The varying dependencies on mTORC1 and Rac1 led us to analyse a potential scaffolding function of p110 beta with Rac1 to mediate phosphorylation and activation of mTOR using platforms for the modeling of biomolecular complexes. We also documented that p110 alpha and p110 beta support cell cycle kinetics differentially. Conclusions This study suggests differential regulation of protein translation, metabolism, cell cycle, and survival signaling downstream of unique p110 targets, underlying the importance of cancer treatment according to the deregulated p110 isoform.
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    Detection of phosphorylation signatures specific to cancer-related PI3-Kinase isoforms p110α and p110β
    (2023-01) Sulaiman, Mahnoor
    The PI3K signaling pathway is required for many physiological activities, but it is commonly disrupted during cancer formation. The PI3K p110α and βisoforms, encoded by the PIK3CA and PIK3CB genes, are lipid kinases that phosphorylate PIP2 to PIP3 to activate the PI3K pathway. However, the distinct molecular targets of these isoforms have yet to be discovered, making targeted treatment problematic. According to cancer genomics research, the PIK3CA gene is commonly altered in cancers, but the PIK3CB gene is frequently amplified. The clinical usage of Pan-PI3K inhibitors has resulted in significant side effects, prompting the development of isoform-specific inhibitors. However, it has been shown that these drugs trigger alternate signaling systems downstream, leading in resistance to single-agent treatment. Our research intends to uncover distinctive protein-protein interactions of PI3K isoforms, as well as the consequent different phospho-proteomic signatures, which might be crucial determinants of specific cellular activities. This will be accomplished by using isogenic MEF cells that are only dependent on the p110α or p110β isoforms, isoform-specific pharmacological inhibitors BYL-719 and KIN 193, and a high-resolution mass spectrometry-based method to determine the phosphorylation levels of these protein samples. The predictive biomarkers discovered in this study can be utilized to identify patients who will benefit from PI3K-targeted drugs and to better understand the resistance mechanisms that may arise in response to pathway inhibition.
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    The International College, Smyrna
    (Bilkent University, 2017) Sulaiman, Mahnoor; Wali Hussain, Syed; Shahid, Gozeel Binte; Sadegova, Shabnam; Khan, Nigel Bruce