ABSTRACT: PPP1R1A, or protein phosphatase 1 regulatory inhibitor subunit 1A, is an essential regulatory protein that plays a pivotal role in various cellular processes, including metabolism, cell division, and signal transduction. This protein primarily functions as an inhibitor of protein phosphatase 1 (PP1), which is a major serine/threonine phosphatase responsible for the dephosphorylation of numerous substrates involved in critical signalling pathways [1]. By regulating PP1 activity, PPP1R1A influences diverse physiological functions, including muscle contraction, neuronal signalling, and insulin secretion. Dysregulation of PPP1R1A has been implicated in several diseases, including type 2 diabetes, cardiovascular diseases, and certain cancers, underscoring its significance in maintaining cellular homeostasis and overall metabolic health [2-5]. Due to its regulatory functions, PPP1R1A is a potential target for therapeutic interventions aimed at restoring normal cellular function in pathological conditions. Our previous research demonstrated that disruption of PPP1R1A in INS-1 cells led to decreased insulin secretion and impaired glucose uptake, accompanied by significant downregulation of key β-cell function genes including Ins1, Ins2, Pcsk1, Pdx1, Mafa, and components of the exocytosis and calcium transport machinery [6]. Importantly, cell viability, reactive oxygen species levels, apoptosis, and proliferation remained unaffected, indicating a specific impact on β-cell functional pathways. Additionally, we found that PPP1R1A expression is regulated by PDX1 and can be upregulated by rosiglitazone treatment. Building upon these findings, our current proteomics analysis serves as a continuation to further elucidate the molecular mechanisms by which PPP1R1A modulates β-cell function and insulin secretion. We examined downstream proteins involved in the affected signalling pathways identified in our proteomics analysis. These findings were subsequently validated by western blotting, which corroborated the alterations in key pathway components, thereby strengthening the evidence of PPP1R1A’s regulatory impact on β-cell molecular networks.
Alexander Giddey 
