FGF2-PI3K-Akt1 signaling
FGF2-PI3K-Akt1 signaling
Overview
The FGF2-PI3K-Akt1 signaling axis refers to the intracellular cascade initiated by fibroblast growth factor 2 (FGF2) binding to its cognate receptors, leading to the activation of phosphoinositide 3-kinase (PI3K) and its downstream effector serine/threonine kinase Akt1 (also known as protein kinase B alpha). This pathway is a central regulator of cell survival, proliferation, differentiation, and metabolism across a wide range of tissue types. Upon FGF2-mediated receptor engagement, PI3K phosphorylates phosphatidylinositol lipids at the plasma membrane, generating second messengers that recruit and activate Akt1. Once activated, Akt1 phosphorylates numerous substrates involved in cell cycle progression, apoptotic suppression, and anabolic signaling, including components associated with mTOR, FOXO transcription factors, and downstream effectors such as MYC and matrix metalloproteinase-9 (MMP9). The pathway intersects extensively with parallel cascades including MAPK/ERK, JAK-STAT, and Wnt/β-catenin signaling, making it a critical node in both normal physiology and pathological conditions such as cancer, metabolic disease, inflammatory disorders, and tissue aging.
The biological relevance of FGF2-PI3K-Akt1 signaling is underscored by its roles in stem cell maintenance and tissue homeostasis. In bone marrow, for instance, FGF2-PI3K-Akt1 activity supports the function of mesenchymal stromal cells, and its dysregulation has been implicated in age-related changes in bone marrow biology. Dysactivation of this pathway—whether through upstream receptor tyrosine kinase mutations, ligand overexpression, or loss of negative regulators such as PTEN—contributes to oncogenesis and treatment resistance, motivating considerable drug discovery efforts targeting PI3K, Akt1, and associated kinases including FGFR1.
Focus of Latest Publications
Recent publications have examined FGF2-PI3K-Akt1 signaling mainly as part of broader PI3K/Akt-centered oncogenic and disease-related networks, using a mix of network pharmacology, molecular docking, molecular dynamics, transcriptomics, single-cell and spatial profiling, metabolomics, and in vitro/in vivo validation. Across these studies, the pathway was repeatedly linked to cell proliferation, migration, invasion, apoptosis, oxidative stress, and treatment response in cancer and metabolic disease models.
In cervical squamous cell carcinoma progression, multi-omics profiling of premalignant and malignant lesions identified ISG15 as a factor synthesized by inflammatory cancer-associated fibroblasts that stabilizes FGF1 and activates the FGF1/FGFR1/PI3K/AKT/mTOR signaling pathway. In this setting, FGFR1 and PI3K/AKT/mTOR inhibitors suppressed cervical cancer cell proliferation in vitro and tumor growth in vivo, supporting a functional role for FGF-linked PI3K/Akt signaling in malignant progression. Related studies in oral squamous cell carcinoma and glioma also implicated Akt1-associated signaling: hippeastrine was reported to inhibit the HSP90/PI3K/Akt/mTOR axis, while scutellarein and Aucan were both shown to suppress PI3K/AKT signaling and reduce tumor cell growth, migration, invasion, and survival.
Several natural products and herbal formulations were investigated as modulators of Akt1-centered signaling. In silico screening of Scutellaria barbata identified apigenin as a strong Akt1-binding flavonoid with stable molecular dynamics behavior. Comparative metabolomic and network pharmacology analyses of Clerodendrum species also highlighted Akt1 and PIK3CA as core docking targets for candidate bioactive ingredients. Shenling Baizhu Powder was associated with Akt1 among its core targets in ulcerative colitis models, with downstream changes in Akt1, p-Akt1, mTOR, and related inflammatory proteins measured in colon tissue. In hepatocellular carcinoma, a synthesized urolithin derivative inhibited phosphorylation of AKT and ERK1/2, consistent with suppression of PI3K/Akt and MAPK signaling.
Outside oncology, Akt1-related signaling was also connected to metabolic regulation. exercise-induced lactate improved insulin resistance in obese mice and adipocytes through GPR81-dependent activation of the IRS1-AKT-GLUT4 pathway, illustrating a non-cancer context in which AKT signaling contributed to glucose uptake and adipokine balance. In lung adenocarcinoma toxicology analyses, Akt1 emerged as one of several hub targets associated with PFAS exposure, although the study focused on predicted toxicological networks rather than direct pathway validation. Overall, these recent publications position FGF2-PI3K-Akt1 signaling within a broader landscape of FGF/PI3K/Akt pathway regulation, with evidence pointing to roles in cancer progression, natural product pharmacology, and metabolic control.