Protein Kinase B

• Protein Kinase B (PKB), or Akt, is a crucial serine/threonine kinase involved in diverse cellular processes.
• It exists in three isoforms (Akt1, Akt2, Akt3), each with specific, yet overlapping, functions.
• PKB plays a central role in cell survival, growth, proliferation, metabolism, and angiogenesis.
• Its activity is primarily regulated by the PI3K/Akt signaling pathway, responding to growth factors and hormones.
• Dysregulation of PKB signaling is strongly associated with the development and progression of various diseases, particularly cancer.

What is Protein Kinase B (PKB)?

Protein Kinase B (PKB), commonly referred to as Akt, is a family of serine/threonine-specific protein kinases that are central to regulating cell survival, proliferation, metabolism, and growth. As a key downstream effector of the phosphoinositide 3-kinase (PI3K) pathway, PKB mediates signals from various growth factors, cytokines, and hormones. There are three highly homologous isoforms of PKB in mammals: Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ), each encoded by a distinct gene and exhibiting unique tissue distribution and specific physiological roles.

The activation of PKB involves its recruitment to the plasma membrane, where it undergoes phosphorylation by upstream kinases, primarily phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycin complex 2 (mTORC2). Once activated, PKB phosphorylates a wide array of substrate proteins, thereby modulating their activity, localization, or stability. This intricate regulatory mechanism ensures precise control over cellular responses to environmental cues, highlighting its importance in maintaining cellular homeostasis.

Protein Kinase B Function and Signaling Pathways

The multifaceted protein kinase B function is essential for maintaining cellular health and responding to external stimuli. One of its primary roles is to promote cell survival by inhibiting apoptosis (programmed cell death). It achieves this by phosphorylating and inactivating pro-apoptotic proteins while activating anti-apoptotic factors. Beyond survival, PKB is a critical regulator of cell growth and proliferation, influencing cell cycle progression and protein synthesis. Its involvement extends to metabolic regulation, where it plays a significant part in glucose uptake, glycogen synthesis, and lipid metabolism, particularly through its effects on insulin signaling.

The core of protein kinase B signaling lies within the PI3K/Akt pathway, a highly conserved intracellular signaling cascade. This pathway is initiated when growth factors or hormones bind to receptor tyrosine kinases (RTKs) on the cell surface, leading to the activation of PI3K. Activated PI3K then generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which recruits PKB to the plasma membrane. Once localized, PKB is activated by phosphorylation, enabling it to phosphorylate numerous downstream targets. This intricate signaling network integrates diverse extracellular signals to orchestrate complex cellular responses.

The crucial protein kinase B role in various physiological and pathological processes is undeniable. Its dysregulation is a hallmark of many human diseases. For instance, hyperactivation of the PI3K/Akt pathway, often due to mutations in components like PI3K or PTEN (a negative regulator of the pathway), is a common event in a significant percentage of human cancers, including breast, prostate, and ovarian cancers. This persistent activation contributes to uncontrolled cell proliferation, resistance to apoptosis, and increased invasiveness, making PKB a prime therapeutic target in oncology. Conversely, insufficient PKB activity can contribute to conditions like insulin resistance and neurodegenerative disorders. Understanding the nuances of PKB’s function and signaling pathways is therefore vital for developing targeted therapies and improving patient outcomes.

• Cell Survival: Inhibits pro-apoptotic proteins (e.g., Bad, FoxO transcription factors) and activates anti-apoptotic proteins.
• Cell Growth and Proliferation: Promotes protein synthesis (via mTORC1) and cell cycle progression.
• Metabolism: Enhances glucose uptake (via GLUT4 translocation) and glycogen synthesis, while regulating lipid metabolism.
• Angiogenesis: Contributes to the formation of new blood vessels, crucial for tumor growth and wound healing.
• Cell Migration: Influences cell motility and invasion, particularly relevant in cancer metastasis.