โ† Back to Part 4

4.3 Enzyme-Linked Receptors

Enzyme-linked receptors are single-pass transmembrane proteins with intrinsic enzymatic activity or direct association with enzymes. They mediate slow, sustained responses (hours to days) through protein phosphorylation cascades and altered gene transcription.

Major Classes

Receptor Tyrosine Kinases (RTKs)

Largest class (~58 RTKs in humans). Intrinsic tyrosine kinase activity phosphorylates target proteins.

  • โ€ข EGF receptor (EGFR/HER family)
  • โ€ข Insulin/IGF receptor
  • โ€ข PDGF receptor
  • โ€ข VEGF receptor (angiogenesis)
  • โ€ข Neurotrophin receptors (Trk family)
  • โ€ข FGF receptors

Receptor Serine/Threonine Kinases

TGF-ฮฒ superfamily receptors (TGF-ฮฒ, BMPs, activins)

Signaling: Type II receptor (constitutive kinase) + Type I receptor (ligand-activated) โ†’ Smad phosphorylation โ†’ gene transcription

Cytokine Receptors (JAK-STAT pathway)

No intrinsic kinase but recruit JAK (Janus kinase) proteins

Examples: Growth hormone, prolactin, erythropoietin, interferons, interleukins

Receptor Guanylyl Cyclases

Catalyze cGMP synthesis from GTP

Examples: ANP (atrial natriuretic peptide) receptor, BNP receptor

RTK Signaling Mechanism

1. Ligand Binding and Dimerization

Growth factor binding โ†’ receptor dimerization โ†’ juxtaposition of cytoplasmic kinase domains

2. Trans-autophosphorylation

Each kinase phosphorylates tyrosine residues on the partner receptor โ†’ activation + creation of docking sites

3. Recruitment of Signaling Proteins

Proteins with SH2 domains or PTB domains bind phospho-tyrosines. Adaptors: Grb2, Shc | Enzymes: PI3K, PLCฮณ, Src family kinases

4. Downstream Cascades

  • โ€ข Ras/MAPK pathway: Grb2-SOS โ†’ Ras-GTP โ†’ Raf โ†’ MEK โ†’ ERK โ†’ gene transcription (proliferation)
  • โ€ข PI3K/Akt pathway: PI3K โ†’ PIP3 โ†’ PDK1 โ†’ Akt โ†’ mTOR, BAD (survival, growth, metabolism)
  • โ€ข PLCฮณ/PKC pathway: PLCฮณ โ†’ IP3/DAG โ†’ Caยฒโบ/PKC (diverse cellular responses)
  • โ€ข JAK/STAT pathway: JAK โ†’ STAT phosphorylation โ†’ dimerization โ†’ nuclear translocation

RTK Inhibitors in Cancer Therapy

EGFR Inhibitors

Small molecules: Erlotinib, gefitinib, osimertinib (NSCLC with EGFR mutations)

Antibodies: Cetuximab, panitumumab (colorectal, head & neck cancer)

HER2 Inhibitors

Antibodies: Trastuzumab (Herceptin), pertuzumab (HER2+ breast cancer)

Small molecules: Lapatinib (HER2 + EGFR dual inhibitor)

BCR-ABL Inhibitors

1st gen: Imatinib (Gleevec) - chronic myeloid leukemia (CML)

2nd gen: Dasatinib, nilotinib (resistance mutations)

VEGFR Inhibitors

Antibodies: Bevacizumab (anti-VEGF, colorectal, NSCLC)

Small molecules: Sunitinib, sorafenib (multi-kinase inhibitors, RCC)

PDGFR Inhibitors

Imatinib (also targets PDGFR, c-KIT), sunitinib (gastrointestinal stromal tumors - GIST)

ALK Inhibitors

Crizotinib, alectinib, brigatinib (ALK+ NSCLC, ALK fusion proteins)

Other Therapeutic Applications

Insulin Receptor

Agonists: Insulin (type 1 diabetes), insulin analogs (lispro, glargine) | Mechanism: RTK activation โ†’ IRS phosphorylation โ†’ PI3K/Akt โ†’ GLUT4 translocation, glycogen synthesis, protein synthesis

JAK Inhibitors

Tofacitinib, baricitinib: Rheumatoid arthritis (block cytokine signaling) | Ruxolitinib: Myelofibrosis (JAK2 mutations)

Erythropoietin Receptor Agonists

EPO, darbepoetin: Anemia (chronic kidney disease, chemotherapy) | JAK-STAT pathway activation โ†’ RBC production

Mechanisms of Resistance

Kinase Domain Mutations

Gatekeeper mutations (e.g., EGFR T790M) reduce drug binding. Requires 2nd/3rd generation inhibitors (osimertinib)

Pathway Redundancy

Activation of alternative RTKs bypasses blockade. Combination therapy targeting multiple pathways

Downstream Mutations

Constitutive activation of Ras, PI3K, BRAF renders RTK inhibition ineffective

Receptor Amplification

Increased receptor expression overwhelms inhibitor. Higher doses or combination therapy needed

โ† 4.2 Ion Channels4.4 Nuclear Receptors โ†’