| Step | Key molecules | Cellular location | Main functional outputs | Key evidence (source, year) |
|---|---|---|---|---|
| Ligand binding and receptor activation | Insulin, insulin receptor (INSR) α2β2 heterotetramer, receptor Tyr1158/Tyr1162/Tyr1163 autophosphorylation sites | Plasma membrane | Initiates insulin signaling by activating the receptor’s intrinsic tyrosine kinase and creating docking sites for adaptor proteins | Sakaguchi 2024; Szablewski 2024; Caturano 2024 (pqac-00000016, pqac-00000021, pqac-00000020) |
| Adaptor recruitment | IRS1/IRS2, Shc, PTB/PH domains, NPEpY972 receptor motif | Inner leaflet of plasma membrane / receptor-proximal cytosol | Couples activated INSR to downstream metabolic and mitogenic pathways | Sakaguchi 2024; Szablewski 2024 (pqac-00000016, pqac-00000021) |
| PI3K activation and PIP3 generation | IRS proteins, PI3K p85/p110, PIP2, PIP3 | Plasma membrane / cytosolic membrane interface | Establishes the main metabolic signaling branch and recruits PDK1/AKT machinery | Sakaguchi 2024; Szablewski 2024; Caturano 2024 (pqac-00000016, pqac-00000017, pqac-00000020) |
| AKT activation | PIP3, PDK1, AKT/PKB, mTORC2 | Plasma membrane then cytosol | Central integration node for glucose uptake, glycogen synthesis, lipogenesis, protein synthesis, and survival signaling | Sakaguchi 2024; Caturano 2024 (pqac-00000016, pqac-00000020) |
| Glucose transporter trafficking | AKT, GLUT4 vesicles, atypical PKC | Cytosol to plasma membrane in muscle/adipose cells | Increases cellular glucose uptake by translocating GLUT4 to the cell surface | Szablewski 2024; Caturano 2024; Sakaguchi 2024 (pqac-00000017, pqac-00000019, pqac-00000016) |
| Glycogen synthesis control | AKT, GSK3, glycogen synthase | Cytosol | Promotes glycogen synthesis by inhibiting GSK3 and relieving inhibition of glycogen synthase | Szablewski 2024; Caturano 2024; Sakaguchi 2024 (pqac-00000017, pqac-00000020, pqac-00000016) |
| Protein synthesis and anabolic signaling | AKT, TSC2, PRAS40, Rheb, mTORC1, 4E-BP1, p70S6K | Cytosol / lysosomal-mTOR signaling compartments | Stimulates protein synthesis, cell growth, and anabolic metabolism | Caturano 2024; Sakaguchi 2024; Szablewski 2024 (pqac-00000020, pqac-00000016, pqac-00000017) |
| Transcriptional regulation of fasting/feeding programs | AKT, FOXO transcription factors, SREBPs | Cytosol and nucleus | Suppresses FOXO-driven gluconeogenic gene expression and promotes lipogenic/anabolic gene programs during feeding | Sakaguchi 2024; Szablewski 2024 (pqac-00000016, pqac-00000017) |
| MAPK mitogenic branch | Shc, Grb2, SOS, Ras, Raf, MEK, ERK/MAPK | Plasma membrane to cytosol to nucleus | Drives growth, proliferation, differentiation, and gene-expression responses distinct from the core metabolic branch | Sakaguchi 2024; Szablewski 2024; Caturano 2024 (pqac-00000016, pqac-00000017, pqac-00000019) |
| Tissue-level physiological outputs | INSR-B (metabolic isoform), PI3K-AKT branch, MAPK branch, eNOS/NO in heart | Whole-body target tissues including liver, muscle, adipose tissue, and heart | Coordinates glucose disposal, reduced hepatic gluconeogenesis, glycogen and lipid storage, protein anabolism, and in cardiomyocytes supports substrate utilization and survival signaling | Szablewski 2024; Caturano 2024 (pqac-00000017, pqac-00000020) |
| Negative feedback / insulin resistance nodes | Serine-phosphorylated IRS, reduced INSR content/activity, mTORC1-GRB10 feedback | Plasma membrane and cytosol | Weakens IRS–PI3K coupling, blunts GLUT4 translocation and glycogen synthesis, and contributes to insulin resistance | Caturano 2024; Szablewski 2024 (pqac-00000019, pqac-00000022) |


*Table: This table summarizes the major steps of insulin receptor signaling downstream of INS-encoded insulin, linking key molecules and cellular locations to metabolic and mitogenic outputs. It is useful for functional annotation because it connects secreted insulin to its principal target-cell mechanisms and physiological effects.*