Tyrosine Kinase

Aka: Tyrosine Kinase, Protein Tyrosine Kinase, Receptor Protein Tyrosine Kinase, Tyrosine Kinase Receptor, Epidermal Growth Factor Receptor, Vascular Endothelial Growth Factor, Fibroblast Growth Factor Receptor, FGFR, EGFR, Human Epidermal Growth Factor, HER1, HER2/neu, VEGF, Mitogen-Activated Protein Kinase Kinase, Mitogen-Activated Extracellular Signal Regulated Kinase, MEK, Mitogen-Activated Protein Kinase, MAPK Signaling Pathway, Extracellular Signal-Regulated Kinase, ERK, TRKa Receptor Signaling Pathway, Tropomyosin Kinase, Polyadenosine Diphosphate Ribose Polymerase, PARP, PIK3CA, Phosphatidylinositol 3-Kinase Catalytic Alpha, ROS1 Protein Tyrosine Kinase, Hedgehog Signaling Pathway, Mammalian Target of Rapamycin Pathway, mTOR Pathway, Janus Kinase

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II. Physiology: General Protein and Tyrosine Kinases

  1. Protein Tyrosine Kinase
    1. Key enzyme in molecular signaling pathway
    2. Protein kinase, that transfers a phosphate from ATP to a Protein's tyrosine Amino Acid
  2. Tyrosine Kinase Receptor
    1. Family of cell surface receptors
    2. Surface receptor responds to specific Ligands (e.g. EGFR, VEGF, HER2/neu)
    3. Intracellular Tyrosine Kinase phosphorylates Tyrosine on Ligand binding to receptor
      1. Triggers intracellular gene expression changes that affect cell differentiation, growth, propagation

III. Physiology: Specific Protein Kinases

  1. Epidermal Growth Factor Receptor (EGFR, HER1, ErbB1)
    1. Tyrosine Kinase that is activated by specific Ligands
    2. Triggers cascade that leads to cell proliferation, invasion and migration
    3. Target for cancer treatments (e.g. Erbitux, Vectibix, Tarceva, Iressa, Tykerb)
  2. Vascular Endothelial Growth Factor (VEGF)
    1. Angiogenesis signaling Protein (VEGFR 2 and VEGFR 3)
      1. Binds to VEGF receptors on Tyrosine Kinases to initiate Angiogenesis
      2. Target in some Targeted Cancer Therapy (e.g. Avastin)
    2. Other functions
      1. Monocyte activation and differentiation (VEGFR 1)
      2. Also used in Age-Related Macular Degeneration as a VEGF Inhibitor Intravitreal Injection
  3. HER2/neu (erbB-2 Receptor, CD340 Antigen)
    1. EGFR related Tyrosine Kinase important in Breast Cancer
    2. Overexpression of HER2/neu may predict worse prognosis and cancer recurrence
    3. Targeted Cancer Therapy examples include Herceptin and Tykerb
  4. Fibroblast Growth Factor Receptor (FGFR)
    1. FGFR2 has 2 isoforms: Mesenchymal (activated by FGF2) and Epithelial (activated by FGF7 and 10)
      1. Mutations are associated with Craniosynostosis (Apert syndrome, crouzon syndrome)
    2. FGFR3 regulates chrondrocyte growth and cell differentiation
      1. Mutations are associated with Achondroplasia, thanatophoric dysplasia as well as neoplasms
    3. Cancers that may express FGFR Activity
      1. Urothelial carcinoma
      2. Hepatocellular Carcinoma
      3. Ovarian Cancer
      4. Lung Adenocarcinoma
  5. Neurotrophic Tropomyosin Receptor Kinase (NTRK ot TRK)
    1. Tropomyosin Receptor Kinase (TRK) is activated by neurotrophic growth factors
    2. When bound, TRKs are activated, triggering a phosphorylation cascade, then triggering the MAPK pathway
  6. ROS1 Tyrosine-Protein Kinase
    1. Proto-oncogene ROS is encoded by the ROS1 gene
    2. ROS is a Protein associated with cell growth, via Tyrosine phosphorylation and receptor-mediated signaling
    3. Member of the sevenless subfamily of Tyrosine Kinase Insulin receptor genes
  7. Cyclin-Dependent Kinase
    1. CDK4 (Cyclin D1) and CDK6 (Cyclin D3) are Serine-Threonine kinases
    2. These kinases become unregulated in some tumor types (e.g. Retinoblastoma), resulting in tumor cell growth
  8. Janus Kinase (JAK) and the JAK/STAT Pathway
    1. Janus Kinase (JAK) is a family of intracellular Tyrosine Kinases that trigger a signaling cascade of Cytokines
    2. JAK acts on STAT transcription factors, triggering gene transcription related to inflammation
    3. Janus Kinase (JAK) is named for its Protein's 2 phosphate-Transferring domains
    4. JAK Inhibitors are used in Rheumatoid Arthritis, Psoriatic Arthritis, Ulcerative Colitis, Polycythemia Vera,

IV. Physiology: Sonic Hedgehog Signaling Pathway

  1. Hedgehog (Hh) family of signaling Proteins
    1. Key role in human development (as well as many other species, including Drosophila)
    2. Regulates tissue and organ morphogenesis, as well as stem cell proliferation in adults
    3. Many cancers involve aberrant activation of the Hh pathway
  2. Components
    1. Fused (Serine/ThreonineProtein kinase)
    2. Coastal 2 or COS2 (kinesin motor Protein)
    3. Gli (zinc finger transcription factor )
  3. Signal cascade
    1. Sonic Hedgehog (SHh) family factors bind PTC (patched)
    2. PTC binding releases SMO (smoothened) as a signal
    3. SMO activates transcription of target genes via the GLI family of Proteins

V. Physiology: MAPK Pathway

  1. Mitogen-Activated Protein Kinase (MAPK) Pathway
    1. Serine and ThreonineProtein kinases triggered extracellularly and encoded by multiple genes
    2. MAPK is a part of a complex cascade of Protein kinases (RAF, MEK, ERK)
  2. Mitogen-Activated Extracellular Signal Regulated Kinase (MEK, MKK, Mitogen-Activated Protein Kinase Kinase)
    1. Serine-ThreonineProtein kinases that phosphorylate and activate MAPK agents
    2. MEK includes a subset of kinases known as JNK Kinases (SAPK Kinases)
  3. Extracellular Signal-Regulated Kinase (ERK)
    1. Activated by the MAPK pathway, ERK enters the cell nucleus where it phosphorylates targets
    2. Includes ERK1 and ERK2
  4. References
    1. Cargnello (2011) Microbiol Mol Biol Rev 75(1):50-83 +PMID: 21372320 [PubMed]

VI. Physiology: Phosphatidylinositol 3-Kinase Pathway (PI3K Path, PIK3CA Gene)

  1. Phosphatidylinositol 3-Kinase Catalytic Alpha (PIK3CA)
    1. PIK3CA gene encodes for Phosphatidylinositol 3-kinases (PI3K), key to cell growth, development and survival
  2. Phosphatidylinositol 3-kinase (PI3K)
    1. Growth factors bind and activate PI3K Tyrosine Kinase, triggering synthesis of PIP3 as a secondary messenger
    2. PIP3 drives many cell processes, including growth, development, apoptosis, adhesion and motility
  3. References
    1. Karakas (2006) Br J Cancer 94(4):455-9 +PMID: 16449998 [PubMed]

VII. Physiology: Mammalian Target of Rapamycin Pathway (mTOR Pathway)

  1. Mammalian Target of RapamycinProtein (mTOR Protein)
    1. Serine-Threonine Kinase composed of a Protein complex (5-6 components) with 2 type (mTOR1, mTOR2)
    2. Regulates Protein synthesis in response to cellular stress
  2. mTOR has multiple associated triggers in pathophysiology
    1. Cancer formation and Angiogenesis
    2. Insulin Resistance and Diabetes Mellitus
    3. Adipogenesis
    4. T-Lymphocyte activation
    5. Ongoing research into mTOR Inhibitors as anti-aging drugs (see mTOR Inhibitor)

VIII. Physiology: Other Small Molecule Targets (not Protein kinase receptors)

  1. General
    1. Most small molecule agents target Tyrosine Kinase and other Protein receptor kinases
    2. Several small molecule Chemotherapy targets are not Protein kinases
  2. Polyadenosine Diphosphate Ribose Polymerase (PARP)
    1. PARP is a group of enzymes (at least 18) that promote ADP ribose transfer to target Proteins
    2. PARP enzymes are key to DNA/RNA function (structure, transcription, replication, recombination, and repair)
    3. DNA repair includes single strand DNA breaks (via base excision repair or BER Pathway)

IX. Resources

  1. Tyrosine Kinase Receptors (StatPearls)
    1. https://www.ncbi.nlm.nih.gov/books/NBK538532/

X. References

  1. Olson (2020) Clinical Pharmacology, Medmaster, Miami, Fl, p. 130-3
  2. Paul (2004) Int J Med Sci 1(2):101-15 +PMID: 15912202 [PubMed]

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