Cell Signaling and Cancer Flashcards

Recap from Lecture 1

• University of Attendance: Kent

Key Types of Signaling

• Endocrine Signaling:

  • Involves signaling cells releasing hormones into the bloodstream that target distant cells.

• Paracrine Signaling:

  • Signaling molecules affect nearby target cells in the vicinity of the signaling cell.

• Neuronal Signaling:

  • Involves direct signaling between nerve cells through neurotransmitters at synapses.

• Contact-Dependent Signaling:

  • Signaling molecules bind to receptors on adjacent cells; requires direct contact.

Intracellular Signaling Pathways

• Functions include:

  • Relay the signal onward.

  • Amplify the signal to create a larger intracellular response with fewer extracellular signals.

  • Integrate signals from multiple pathways before transmission.

  • Distribute signals to various effector proteins for complex responses.

  • Engage in feedback mechanisms to modulate signal response through regulation of upstream components.

Types of Cell Surface Receptors

• Ion-channel-coupled receptors

• G-protein-coupled receptors (GPCRs)

• Enzyme-coupled receptors

Molecular Switches in Signaling

• Molecular switches act as on/off mechanisms:

  • Signal reception triggers a switch from inactive to active state.

• Two classes of switches:

  • Activated by phosphorylation.

  • GTP binding proteins.

Enzyme-Coupled Receptors

• Act as enzymes or associate with enzymes.

• Binding signal molecules activates enzyme activity inside the cell.

• Some possess intrinsic enzyme activity, while others rely on associated enzymes.

Receptor Tyrosine Kinases (RTKs)

• Largest class of enzyme-coupled receptors.

• Tyrosine kinases phosphorylate specific intracellular signaling proteins, including themselves.

Activation of RTKs

• Steps of RTK activation:

  1. Binding of a signal molecule induces dimerization.

  2. Dimerization activates kinases to phosphorylate adjacent receptor tails.

  3. Phosphorylated residues act as docking sites for intracellular signaling proteins.

  4. RTKs typically activate the Ras GTPase.

  5. Specialized domains like SH2 recognize phosphorylated tyrosines, relaying signals inside the cell.

Ras and Signal Pathways

• Ras GTPase:

  • Cycles between GTP-bound (active) and GDP-bound (inactive) states.

  • Activated by adaptor proteins and stimulates downstream signaling pathways.

  • Contains a lipid group aiding membrane anchoring.

Kinases and Their Function

• Kinase: Enzymes that add phosphate groups to substrates (e.g., proteins, lipids).

• Essential types include:

  • Protein Kinase: Phosphorylates proteins (serine/theronine/tyrosine).

  • Lipid Kinase: Phosphorylates lipids (e.g., conversion of PIP2 to PIP3).

MAP Kinase Signaling Pathway

• Activated Ras leads to a phosphorylation cascade, signaling from the membrane to the nucleus through a three-kinase module (MAP-kinase signaling module).

PI 3-Kinase Pathway

• Phosphoinositide 3-kinase (PI 3-kinase):

  • A lipid kinase phosphorylating PIP2 to PIP3, attracting signaling proteins to activate them.

  • Akt is a crucial serine/threonine kinase in this process.

Role of IGF in Signaling

• Insulin-like Growth Factor (IGF) activates RTK (IGFR) enhancing PI 3-kinase activity, leading to signaling through Akt.

Signaling Pathways and Cancer

• Many components of signaling pathways are mutated in cancers, including:

  • RTKs (e.g., IGFR, EGFR, HER2)

  • Ras GTPase, MAPK cascade, PI3K, and AKT.

  • About 30% of cancers have Ras mutations.

Characteristics of Cancer

• Cancer is characterized by uncontrolled cell division and can spread to other tissues.

• More than 200 types of cancer exist since there are over 200 different cell types in the human body.

• 1 in 2 people in the UK will develop cancer in their lifetime.

  • Advances in research lead to better detection, diagnosis, and treatment options.

Causes of Cancer

• Cancer primarily arises from genetic mutations, particularly somatic mutations within individual somatic cells.

Risk Factors for Cancer

• Factors include:

  • Genetic inheritance.

  • Environmental exposure: UV rays, smoking, alcohol.

  • Lifestyle choices: Diet, exercise, lack thereof.

Research on RTKs, PI 3-Kinase, and AKT in Cancer

• Mutations in RTKs, PI3K, AKT, and PTEN are common in cancers.

  • PTEN dephosphorylates PIP3, regulating signaling pathways.

  • Drugs can target active mutated forms of these proteins.

Understanding Cancer Cell Biology

• Targeting deregulated proteins (e.g., AKT) can lead to innovative cancer treatments.

Drug Discovery Process

• Involves multidisciplinary collaboration across various fields (biology, chemistry, mathematics, and clinical sectors).

Example of AKT Drug Discovery Project

• Led by researchers at ICR, focusing on developing targeted cancer therapies like capivasertib, which received FDA approval in November 2023.

Summary of Key Points

• Three types of cell surface receptors are critical for signaling pathways.

• RTKs play a pivotal role in regulating intracellular signaling pathways that are involved in cancer.

• Targeting mutated proteins in these pathways can lead to effective cancer treatments.