1.4 Signal transduction pathways

Signal transduction pathways are crucial for cells to respond to external stimuli and communicate. These pathways involve various components and mechanisms, including cell surface receptors, intracellular receptors, and second messengers like cAMP and calcium.

Understanding these pathways is essential for developing targeted therapies in medicinal chemistry. Different types of pathways exist, each with unique components and mechanisms of action, allowing cells to respond to a wide range of signals and regulate various cellular processes.

Types of signal transduction pathways

• Signal transduction pathways are essential for cells to respond to external stimuli and communicate with each other
• Different types of pathways exist, each with unique components and mechanisms of action
• Understanding these pathways is crucial for developing targeted therapies in medicinal chemistry

Receptor-mediated signal transduction

Cell surface receptors

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• Cell surface receptors are proteins embedded in the plasma membrane that bind extracellular ligands (hormones, neurotransmitters, growth factors)
• Ligand binding induces conformational changes in the receptor, leading to activation of intracellular signaling cascades
• Examples of cell surface receptors include G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and ion channel-linked receptors

Intracellular receptors

• Intracellular receptors are located within the cytoplasm or nucleus and bind to lipophilic ligands that can diffuse across the plasma membrane (steroid hormones, thyroid hormones, retinoic acid)
• Ligand binding causes the receptor to translocate to the nucleus and directly regulate gene expression
• Examples of intracellular receptors include steroid hormone receptors (estrogen receptor, glucocorticoid receptor) and nuclear receptors (thyroid hormone receptor, retinoic acid receptor)

Receptor activation and deactivation

• Receptor activation occurs when a ligand binds to the receptor, inducing conformational changes that initiate signaling cascades
• Deactivation of receptors is essential for regulating the duration and intensity of signaling
• Mechanisms of receptor deactivation include ligand dissociation, receptor internalization, and degradation

Second messengers in signal transduction

cAMP signaling pathway

• Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that amplifies and propagates signals from GPCRs
• Activation of Gs-coupled receptors stimulates adenylyl cyclase, which converts ATP to cAMP
• cAMP activates protein kinase A (PKA), which phosphorylates various downstream targets to regulate cellular processes (glycogen metabolism, gene expression)

Calcium signaling pathway

• Calcium (Ca2+) is a versatile second messenger involved in numerous cellular processes (muscle contraction, neurotransmitter release, cell proliferation)
• Intracellular Ca2+ levels are tightly regulated by ion channels, pumps, and exchangers
• Activation of Gq-coupled receptors leads to the release of Ca2+ from the endoplasmic reticulum via the IP3 receptor, while voltage-gated Ca2+ channels mediate Ca2+ influx from the extracellular space

Phosphoinositide signaling pathway

• Phosphoinositides are membrane lipids that serve as substrates for phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K)
• Activation of Gq-coupled receptors stimulates PLC, which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)
• IP3 triggers Ca2+ release from the endoplasmic reticulum, while DAG activates protein kinase C (PKC), which phosphorylates various downstream targets

Protein kinases in signal transduction

Serine/threonine kinases

• Serine/threonine kinases phosphorylate serine or threonine residues on target proteins
• Examples include PKA, PKC, and mitogen-activated protein kinases (MAPKs)
• These kinases play crucial roles in regulating cell growth, differentiation, and survival

Tyrosine kinases

• Tyrosine kinases phosphorylate tyrosine residues on target proteins
• They can be classified as receptor tyrosine kinases (RTKs) or non-receptor tyrosine kinases (NRTKs)
• RTKs (insulin receptor, epidermal growth factor receptor) are cell surface receptors that dimerize upon ligand binding and autophosphorylate, while NRTKs (Src, Abl) are cytoplasmic enzymes that associate with activated receptors

Kinase cascades

• Kinase cascades are series of sequentially activated protein kinases that amplify and diversify signals
• The MAPK cascade is a well-characterized example, consisting of three tiers: MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK
• Kinase cascades allow for precise regulation of cellular responses and integration of multiple signaling pathways

Transcription factors in signal transduction

Activation of transcription factors

• Transcription factors are proteins that bind to specific DNA sequences and regulate gene expression
• Many signaling pathways ultimately lead to the activation of transcription factors through phosphorylation, dephosphorylation, or translocation to the nucleus
• Examples of transcription factors include CREB (cAMP response element-binding protein), NF-κB (nuclear factor kappa B), and STAT (signal transducer and activator of transcription)

Regulation of gene expression

• Activated transcription factors bind to promoter or enhancer regions of target genes and recruit coactivators or corepressors to modulate transcription
• Signal transduction pathways can induce both short-term changes in gene expression (immediate early genes) and long-term changes (late response genes)
• Dysregulation of transcription factor activity can lead to various diseases, including cancer and inflammatory disorders

Crosstalk between signaling pathways

• Crosstalk refers to the interaction and integration of different signaling pathways within a cell
• Pathways can converge on common downstream targets (transcription factors, effector proteins) or modulate each other's activity through feedback loops
• Crosstalk allows for fine-tuning of cellular responses and adaptation to complex environmental cues
• Examples of crosstalk include the interaction between the MAPK and PI3K pathways in regulating cell survival and proliferation

Feedback loops in signal transduction

Positive vs negative feedback

• Feedback loops are regulatory mechanisms that allow signaling pathways to self-modulate based on their output
• Positive feedback loops amplify signals and can lead to rapid, switch-like responses (blood clotting cascade)
• Negative feedback loops attenuate signals and maintain homeostasis (regulation of blood glucose by insulin and glucagon)
• Disruption of feedback loops can contribute to disease states, such as insulin resistance in type 2 diabetes

Diseases associated with signal transduction

Cancer and aberrant signaling

• Cancer often arises from mutations in genes encoding signaling proteins, leading to constitutive activation or loss of regulation
• Examples include activating mutations in RTKs (EGFR in lung cancer) or downstream effectors (BRAF in melanoma), and loss of tumor suppressors (PTEN in various cancers)
• Aberrant signaling promotes uncontrolled cell proliferation, survival, and metastasis

Neurodegenerative disorders

• Neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, involve dysregulation of signaling pathways in neurons
• Accumulation of misfolded proteins (amyloid-beta, alpha-synuclein) can disrupt synaptic transmission and activate inflammatory signaling cascades
• Impaired neurotrophic signaling (BDNF, NGF) can contribute to neuronal death and cognitive decline

Autoimmune diseases

• Autoimmune diseases result from inappropriate activation of immune signaling pathways against self-antigens
• Cytokine signaling plays a central role in the pathogenesis of autoimmune disorders, such as rheumatoid arthritis and multiple sclerosis
• Dysregulated T cell and B cell receptor signaling can lead to the production of autoantibodies and chronic inflammation

Therapeutic targeting of signal transduction

Small molecule inhibitors

• Small molecule inhibitors are synthetic compounds designed to selectively block the activity of signaling proteins
• Examples include kinase inhibitors (imatinib for chronic myeloid leukemia, gefitinib for EGFR-mutant lung cancer) and GPCR antagonists (beta-blockers for hypertension)
• Challenges in developing small molecule inhibitors include achieving selectivity, overcoming resistance mechanisms, and managing side effects

Monoclonal antibodies

• Monoclonal antibodies are engineered proteins that bind to specific targets, such as cell surface receptors or secreted ligands
• They can block ligand-receptor interactions, induce receptor internalization, or activate immune-mediated cytotoxicity
• Examples include trastuzumab for HER2-positive breast cancer and infliximab for rheumatoid arthritis and inflammatory bowel disease

Gene therapy approaches

• Gene therapy involves the introduction of genetic material into cells to modulate the expression of signaling proteins
• Strategies include delivering tumor suppressor genes (p53), silencing oncogenes with RNA interference (siRNA against BCR-ABL), or introducing chimeric antigen receptors (CAR-T cells)
• Gene therapy holds promise for treating genetic disorders and cancer, but challenges remain in terms of delivery, safety, and long-term efficacy