The PI3K-PKB/Akt pathway, initially identified in the early 1980s through studies on insulin receptor signaling, has evolved into a well-studied and highly conserved signaling pathway. This pathway is activated by receptor tyrosine kinases (RTKs) via the insulin receptor substrate (IRS) proteins, leading to the activation of phosphoinositide-3-kinase (PI3K) and subsequent conversion of phosphatidylinositol (3,4)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PKB/Akt binds to PIP3, allowing 3-phosphoinositide-dependent protein kinase 1 (PDK1) to phosphorylate PKB/Akt at threonine 308, initiating its activation. Further phosphorylation at serine 473 by mTOR or DNA-PK completes the activation process. Fully active PKB/Akt mediates various cellular functions, including angiogenesis, metabolism, growth, proliferation, survival, protein synthesis, transcription, and apoptosis. Negative regulators such as protein phosphatase 2A (PP2A), phosphatase and tensin homolog (PTEN), and PH-domain leucine-rich-repeat-containing protein phosphatases (PHLPP1/2) antagonize Akt signaling by dephosphorylating specific residues. The pathway's regulation and its role in tumorigenesis have been extensively studied, contributing to our understanding of cellular processes and therapeutic targets.The PI3K-PKB/Akt pathway, initially identified in the early 1980s through studies on insulin receptor signaling, has evolved into a well-studied and highly conserved signaling pathway. This pathway is activated by receptor tyrosine kinases (RTKs) via the insulin receptor substrate (IRS) proteins, leading to the activation of phosphoinositide-3-kinase (PI3K) and subsequent conversion of phosphatidylinositol (3,4)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PKB/Akt binds to PIP3, allowing 3-phosphoinositide-dependent protein kinase 1 (PDK1) to phosphorylate PKB/Akt at threonine 308, initiating its activation. Further phosphorylation at serine 473 by mTOR or DNA-PK completes the activation process. Fully active PKB/Akt mediates various cellular functions, including angiogenesis, metabolism, growth, proliferation, survival, protein synthesis, transcription, and apoptosis. Negative regulators such as protein phosphatase 2A (PP2A), phosphatase and tensin homolog (PTEN), and PH-domain leucine-rich-repeat-containing protein phosphatases (PHLPP1/2) antagonize Akt signaling by dephosphorylating specific residues. The pathway's regulation and its role in tumorigenesis have been extensively studied, contributing to our understanding of cellular processes and therapeutic targets.