What are signal molecules? How do defects in signalling pathway cause pathological changes?

Signal Molecules and Signaling Pathways

Signal molecules can be broadly categorized into several classes, including hormones, growth factors, neurotransmitters, cytokines, and chemokines. These molecules exert their effects by binding to specific receptors, which can be located on the cell surface (e.g., G protein-coupled receptors, receptor tyrosine kinases) or intracellularly (e.g., steroid hormone receptors). Upon receptor activation, a signaling cascade is initiated, involving a series of protein-protein interactions and post-translational modifications (phosphorylation, ubiquitination, etc.). This cascade ultimately leads to changes in gene expression, protein activity, or cellular metabolism.

Defects in Signaling Pathways and Pathological Changes

Defects in signaling pathways can occur at any stage – reception, transduction, or response – leading to diverse pathological consequences. Here's a breakdown:

1. Defects in Reception

• Receptor Mutations: Mutations in receptor genes can alter receptor structure, leading to constitutive activation (always ‘on’) or inactivation (unable to bind ligand). For example, mutations in the EGFR (Epidermal Growth Factor Receptor) gene are frequently found in non-small cell lung cancer, resulting in uncontrolled cell proliferation.
• Autoantibody Production: Autoantibodies targeting receptors can either activate or block signaling. In Graves’ disease, autoantibodies bind to the TSH receptor, mimicking TSH and causing hyperthyroidism. Conversely, in myasthenia gravis, autoantibodies block acetylcholine receptors at the neuromuscular junction, leading to muscle weakness.
• Ligand Deficiency/Excess: Insufficient or excessive production of signaling molecules can disrupt normal signaling. Type 1 diabetes results from the autoimmune destruction of pancreatic beta cells, leading to insulin deficiency and impaired glucose uptake.

2. Defects in Signal Transduction

• Mutations in Kinases/Phosphatases: Kinases and phosphatases regulate protein phosphorylation, a key mechanism in signal transduction. Mutations in these enzymes can disrupt signaling cascades. For instance, mutations in the RAS gene, a small GTPase involved in multiple signaling pathways, are common in various cancers, leading to uncontrolled cell growth.
• Dysregulation of Second Messengers: Second messengers like cAMP, calcium ions, and IP3 amplify and diversify signaling. Defects in their production or degradation can alter signaling. Mutations affecting adenylate cyclase, which produces cAMP, can disrupt hormone signaling.
• G-Protein Mutations: G-proteins mediate signaling from G protein-coupled receptors. Mutations can lead to constitutive activation or inactivation of downstream effectors.

3. Defects in Cellular Response

• Transcription Factor Mutations: Transcription factors regulate gene expression. Mutations can alter their ability to bind DNA or interact with co-factors. Mutations in the p53 tumor suppressor gene, a key transcription factor involved in cell cycle arrest and apoptosis, are found in over 50% of human cancers.
• Downstream Target Gene Mutations: Mutations in genes regulated by signaling pathways can disrupt the cellular response.
• Epigenetic Modifications: Alterations in DNA methylation or histone modification can affect gene expression and cellular response to signals.

Examples of Diseases Linked to Signaling Defects

Disease	Affected Pathway	Defect
Cancer	RAS/MAPK, PI3K/AKT/mTOR	Activating mutations in RAS, loss of PTEN (a negative regulator of PI3K)
Type 2 Diabetes	Insulin Signaling	Insulin resistance due to defects in insulin receptor signaling or downstream targets
Alzheimer’s Disease	Wnt Signaling, Notch Signaling	Dysregulation of signaling pathways involved in neuronal development and synaptic plasticity
Autoimmune Diseases (e.g., Rheumatoid Arthritis)	Cytokine Signaling (e.g., TNF-α, IL-6)	Overproduction of pro-inflammatory cytokines and dysregulation of immune cell signaling