Signal Transduction and Receptor Kinases

Introduction

  • Class began with an announcement about donuts for a food drive (BBFD).

  • Students encouraged to grab donuts after class.

Overview of Signal Transduction

  • Focus on the process of signal transduction, particularly on receptor types involved.

  • Importance of understanding different types of receptors:

    • G protein-coupled receptors (GPCRs)

    • Receptor tyrosine kinases (RTKs)

Basic Concepts of Signal Transduction

  • General idea: Ligand binds to a receptor, triggering a cellular response.

  • Previous discussion on GPCRs included:

    • Ligand binding recruits G proteins (Gα, Gβ, Gγ), initiating a cascade:

      • Exchange of GDP for GTP on Gα.

      • Gα typically activates downstream signaling events.

Receptor Tyrosine Kinases (RTKs)

Structure and Function

  • Membrane-bound receptors capable of ligand binding and signal propagation through a kinase domain.

    • Kinases add phosphate groups to target molecules, functioning like a switch.

    • Most kinases (\text{act as switches, being inactive (unphosphorylated) in their off position.})

  • Activation Cycle:

    • Kinases are activated through phosphorylation (e.g., transferring phosphate from ATP).

    • Signal activation requires the ability to also turn off (via phosphatases).

    • Phosphatases remove phosphate groups.

Amino Acids Involved in Phosphorylation

  • Of the 20 standard amino acids, only three can be phosphorylated:

    • Tyrosine (by tyrosine kinases)

    • Serine and Threonine (by serine/threonine kinases).

    • Specificity noted for tyrosine kinases and dual specificity kinases (can phosphorylate serine and/or threonine).

Activation Mechanism of RTKs

  1. Ligand binds to receptor, initiating dimerization (receptor clustering).

  2. Autophosphorylation occurs as kinases phosphorylate their own tyrosines.

  3. Activated receptors recruit signaling proteins to propagate the cascade.

  4. Example: GSK3 is turned off upon phosphorylation by AKT (a central node kinase).

    • Note: Phosphorylation does not always equal activation; exceptions exist.

Growth Factors and Cell Culture

Historical Context of Cell Culture

  • Initial attempts to grow cells used blood plasma, but resulted in cell death.

  • Blood serum was determined to effectively support cell culture due to its growth factors, chiefly produced by platelets during clotting:

    • Platelet-Derived Growth Factor (PDGF)

    • Other examples include EGF (Epidermal Growth Factor) and NGF (Nerve Growth Factor).

Signal Cascades from RTKs

Example with EGF

  • EGF binds its receptor, promoting:

    • Dimerization

    • Autophosphorylation, leading to activation of key proteins:

      • Grb2 (recruits SOS, facilitating exchange of GDP for GTP on RAS).

      • Phospholipase C-gamma, producing inositol triphosphate (IP3).

      • RAS activates RAF, MEK, MAP kinase, leading to gene expression changes.

      • Signal termination can occur via several mechanisms (removal of the ligand, downregulation of receptors).

MAP Kinase Cascade

  • Important for signal transduction involving coordinated activation of kinases and transcription factors:

    • MAPK module organized with scaffolding proteins to enhance efficiency and accuracy of signaling.

    • Kinases cascade (RAF, MEK, MAP kinase) leads to transcription factor activation.

Crosstalk and Signal Integration

Concept of Crosstalk

  • Various signaling pathways can intersect and influence each other, enhancing complexity and control within cellular signaling.

  • Scaffold proteins help organize kinases for efficient signal propagation by keeping them in close proximity.

Challenges in Signal Transduction

  • Maintaining balance in signaling pathways remains crucial, especially in cancer contexts:

    • Goal is to inhibit specific pathways without affecting normal cellular functions significantly.

Hormonal Signaling

Characteristics of Hormonal Signaling

  • Endocrine signaling characterized by long-distance signaling through hormones (e.g., adrenaline).

  • Hormones can bind to cytoplasmic receptors due to their hydrophobic nature.

  • Example: Mechanism of adrenal response to stress through hormones like adrenaline, which varies between tissues.

Example of Nitric Oxide (NO) as a Signaling Molecule

  • Synthesized from arginine through the action of nitric oxide synthase, influencing blood flow (dilation) via production of cyclic GMP.

  • Medical context: Nitroglycerin uses this pathway to relieve angina by promoting NO synthesis.