Defects in Signaling Pathway and Consequences | Zoology Optional Notes for UPSC PDF Download

Introduction

In light of the intricate nature of signal-transduction pathways, it is not surprising that occasional failures in these pathways can result in pathological or disease states. One such disease closely associated with defects in signal-transduction proteins is cancer, characterized by uncontrolled cell growth. The study of cancer, particularly those caused by viruses, has significantly contributed to our understanding of signal-transduction proteins and pathways.

1. Viral Oncogenes and the Example of Rous Sarcoma Virus:

• Rous sarcoma virus, a retrovirus causing sarcoma in chickens, carries the oncogene v-src.
• The v-src gene encodes a protein tyrosine kinase with SH2 and SH3 domains.
• The v-Src protein, similar to c-Src, is an oncogene, while c-Src is a proto-oncogene.
• Small differences in amino acid sequences lead to the oncogene being constitutively active.
• The inactive conformation of c-Src involves intricate interactions between SH2, SH3, and kinase domains.

2. Activation Mechanisms of Src Protein:

• Src can be activated by displacing the phosphotyrosine residue in the SH2 domain.
• Phosphorylation on the tyrosine residue can be removed by a phosphatase.
• The linker between the SH2 and kinase domain can be displaced by a polypeptide.
• Src responds to distinct signals, exhibiting flexibility in its activation mechanism.

3. Mutation in Oncogenes and Biological Activity:

• Despite more than 90% amino acid sequence identity, the viral oncogene exhibits different biological activity.
• The C-terminal region of c-Src is replaced by a different stretch lacking a key tyrosine residue.
• Mutated protein kinases, including Src, are identified as oncogenes.

4. Acquisition of Mutated Version by Rous Sarcoma Virus:

• Infection allows a viral genome to pick up a host gene with a missing region encoding the last few amino acids.
• The modified gene may confer a selective advantage, favoring viral growth upon introduction to a host cell.

5. Impaired GTPase Activity and Ras in Cancer:

• Mutations in ras genes are common in human tumors.
• Ras proteins cycle between GTP and GDP forms, and mutations often lead to impaired GTPase activity.
• Ras protein remains constitutively active, contributing to cancer progression.

6. Protein Kinase Inhibitors as Anticancer Drugs:

• Overactive protein kinases in cancer cells suggest potential targets for anticancer drugs.
• In chronic myelogenous leukemia (CML), a specific inhibitor of the Bcr-Abl kinase has shown significant efficacy.
• Clinical trials demonstrate more than 90% positive response, offering a distinct approach to cancer chemotherapy.
  

Cholera Toxin and G-Protein Dysregulation

• Cholera, an acute diarrheal disease, is caused by Vibrio cholera.
• Choleragen, the cholera toxin, consists of B and A subunits.

Mechanism of Action:

• B subunit binds to G M1 gangliosides, facilitating cell entry of the catalytic A subunit.
• A subunit modifies Gs protein, attaching ADP-ribose to an arginine residue.
• Modification stabilizes GTP-bound Gs, perpetually activating the signal-transduction pathway.
• Continuous activation of protein kinase A (PKA) leads to chloride channel opening and Na+-H+ exchanger inhibition.
• Result: Excessive loss of NaCl and water into the intestine.

• Clinical Impact:

  • Cholera patients may lose as much as twice their body weight in fluid.
  • Treatment involves rehydration with a glucose-electrolyte solution.

Pertussis Toxin and G-Protein Inhibition

Pertussis (whooping cough) is caused by Bordetella pertussis, secreting pertussis toxin.

• Mechanism of Action:

  • Pertussis toxin adds an ADP-ribose moiety to Gi protein.
  • Gi protein normally inhibits adenyl cyclase, closes Ca2+ channels, and opens K+ channels.
  • Modification lowers Gi protein's affinity for GTP, trapping it in the "off" conformation.

• Clinical Impact:

  • Pulmonary symptoms in pertussis are not yet linked to a specific G protein target.

G-Protein-Related Diseases

Overview:

• Cholera and pertussis represent only two examples of G-protein-related diseases.
• Given that G proteins relay signals for over 500 receptors, more diseases are likely to emerge.
  

Src Protein Structure and Activation

Overview:

• Src protein includes SH3, SH2, protein kinase domains, and a carboxyl-terminal tail with a key tyrosine residue.

• Inactive Conformation:

  • Inactive c-Src has phosphorylated tyrosine bound in the SH2 domain; SH3 domain holds kinase domain inactive.
  • Activation pathways: (1) SH2 domain displacement, (2) dephosphorylation, (3) SH3 domain displacement.

Bcr-Abl Gene Translocation in Chronic Myelogenous Leukemia

• Background:

  • Chromosomes 9 and 22 translocation causes the fusion of bcr and abl genes.
  • Protein kinase encoded by bcr-abl is overexpressed compared to c-abl in normal cells.

• Clinical Implications:

  • Higher expression of Bcr-Abl in leukemia cells offers a unique target for chemotherapy.
  • Clinical trials with Bcr-Abl kinase inhibitors show promising results, with over 90% positive responses.

Diseases of Heterotrimeric G Proteins

• Excessive Signaling:
  • Cholera:
    • Acute diarrheal disease caused by Vibrio cholera.
    • Choleragen toxin modifies Gs protein, leading to perpetual activation of the signal-transduction pathway.
    • Results in voluminous secretion of electrolytes and fluids in the intestines.
  • Cancer (Adenoma) of Pituitary and Thyroid:
    • Overactive G protein signaling associated with adenoma formation.
  • Essential Hypertension:
    • Abnormal G protein signaling implicated in hypertension.
• Deficient Signaling:
  • Night Blindness:
    • Impaired G protein signaling affecting vision in low-light conditions.
  • Pseudohypoparathyroidism Type Ib:
    • G protein-related deficiency causing symptoms resembling hypoparathyroidism.
  • Pertussis:
    • Whooping cough caused by Bordetella pertussis, secreting pertussis toxin.
    • Toxin modifies Gi protein, inhibiting adenyl cyclase and impacting calcium and potassium channels.

Evolutionary Relationships in Signal-Transduction Pathways

1. Ancient Features:

• cAMP Signaling:
  • Ancient signaling molecule for energy needs in prokaryotes and eukaryotes.
  • Different mechanisms for detecting cAMP in prokaryotes and eukaryotes.
• GTP-Binding Proteins:
  • G subunits of heterotrimeric G proteins and Ras family members part of an ancient superfamily.
  • Superfamily includes proteins involved in ATP synthesis, molecular motion, and protein synthesis.
  • These proteins function as molecular "on-off" switches.

2. Early Evolution of Switch Domain:

• Domain allowing conformational changes on binding and hydrolyzing nucleoside triphosphates.
• Likely originated early in evolution and adapted for various biochemical functions.
• Later Evolutionary Developments:
  • Eukaryotic Protein Kinases:
    • Among the largest protein families in eukaryotes, absent in prokaryotes.
    • Evolution of the protein kinase domain a significant step in the emergence of eukaryotes and multicellular organisms.
  • Conservation of Signaling Pathways:
    • Examples like the EGF signal-transduction pathway in Drosophila conserved in mammals.
    • Indicates pathway wiring at least 800 million years old.
      

Conclusion

Understanding diseases associated with heterotrimeric G proteins provides crucial insights into both excessive and deficient signaling. Exploring the evolutionary relationships in signal-transduction pathways reveals ancient features that have been conserved across diverse organisms, highlighting the remarkable complexity and adaptability of these molecular systems over millions of years.