20.2 Receptor Tyrosine Kinases and Signal Transduction

Receptor tyrosine kinases (RTKs) are crucial players in cell signaling. They sit on cell surfaces, waiting for specific molecules to bind. When activated, RTKs kick off a chain reaction inside the cell, telling it to grow, divide, or change.

This process involves many steps and proteins working together. The Ras-MAPK pathway is a key part, carrying the signal from the cell surface to the nucleus. Other pathways like PI3K-Akt and JAK-STAT also play important roles in cell communication.

Receptor Tyrosine Kinases and Activation

Structure and Function of RTKs

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• Receptor tyrosine kinases (RTKs) consist of extracellular, transmembrane, and intracellular domains
• Extracellular domain binds specific ligands (growth factors, hormones)
• Transmembrane domain anchors RTK in cell membrane
• Intracellular domain contains tyrosine kinase activity for signal transduction
• RTKs function as cell surface receptors for various growth factors and hormones
• Activation of RTKs initiates complex signaling cascades regulating cell growth, differentiation, and survival

Mechanism of RTK Activation

• Ligand binding induces RTK dimerization or oligomerization
• Dimerization brings intracellular kinase domains into close proximity
• Autophosphorylation occurs when tyrosine residues on one RTK are phosphorylated by its partner
• Phosphorylated tyrosines serve as docking sites for downstream signaling proteins
• Autophosphorylation enhances kinase activity and creates binding sites for other proteins
• Process amplifies initial signal and allows for recruitment of multiple signaling molecules

Protein Interactions in RTK Signaling

• SH2 (Src Homology 2) domains recognize and bind to specific phosphotyrosine motifs
• SH2 domains found in various signaling proteins (Grb2, PI3K, Src family kinases)
• Adaptor proteins contain multiple protein-binding domains (SH2, SH3, PH)
• Grb2 adaptor protein links activated RTKs to Ras signaling pathway
• Adaptor proteins facilitate formation of signaling complexes and cross-talk between pathways
• Protein-protein interactions mediated by SH2 domains and adaptor proteins crucial for signal transduction

Ras and MAP Kinase Signaling

Ras Protein Activation and Function

• Ras proteins belong to small GTPase superfamily
• Ras cycles between inactive GDP-bound and active GTP-bound states
• Guanine nucleotide exchange factors (GEFs) promote GDP to GTP exchange, activating Ras
• GTPase-activating proteins (GAPs) stimulate GTP hydrolysis, inactivating Ras
• Activated Ras interacts with multiple effector proteins (Raf, PI3K, RalGEF)
• Ras proteins play central role in transmitting signals from RTKs to various downstream pathways

MAP Kinase Cascade Components and Mechanism

• MAP kinase cascade consists of three-tiered kinase system: MAPKKK, MAPKK, MAPK
• Raf (MAPKKK) activates MEK (MAPKK) through phosphorylation
• MEK activates ERK (MAPK) through dual phosphorylation on threonine and tyrosine residues
• Activated ERK phosphorylates various cytoplasmic and nuclear targets
• Scaffold proteins (KSR) enhance efficiency and specificity of MAPK cascade
• Multiple feedback loops and cross-talk mechanisms regulate MAPK signaling intensity and duration

Growth Factor Signaling through Ras-MAPK Pathway

• Growth factors (EGF, PDGF, FGF) bind to specific RTKs on cell surface
• RTK activation leads to recruitment of Grb2-SOS complex to plasma membrane
• SOS acts as GEF for Ras, promoting its activation
• Activated Ras initiates MAP kinase cascade through Raf recruitment and activation
• ERK translocation to nucleus regulates transcription factors controlling cell proliferation and differentiation
• Ras-MAPK pathway integrates multiple inputs to modulate cellular responses to growth factors

Other RTK Signaling Pathways

PI3K-Akt Pathway Mechanism and Functions

• Phosphatidylinositol 3-kinase (PI3K) activated by RTKs or Ras
• PI3K phosphorylates membrane lipid PIP2 to generate PIP3
• PIP3 recruits Akt (protein kinase B) to plasma membrane
• Akt activated by phosphorylation through PDK1 and mTORC2
• Activated Akt phosphorylates numerous substrates involved in cell survival, metabolism, and growth
• PI3K-Akt pathway regulates glucose metabolism, protein synthesis, and apoptosis inhibition
• PTEN phosphatase acts as negative regulator of PI3K-Akt signaling

JAK-STAT Pathway Components and Signaling

• Janus kinases (JAKs) associate with cytokine receptors
• Ligand binding induces receptor dimerization and JAK activation
• Activated JAKs phosphorylate receptor cytoplasmic tails, creating docking sites for STATs
• Signal transducers and activators of transcription (STATs) recruited to phosphorylated receptors
• JAKs phosphorylate STATs, promoting their dimerization and nuclear translocation
• STAT dimers bind to specific DNA sequences and regulate gene expression
• JAK-STAT pathway mediates responses to various cytokines and growth factors
• Negative regulators (SOCS, PIAS) control duration and intensity of JAK-STAT signaling