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The origin of cancer What is cancer? Cancer Research UK defines it as: “… when abnormal cells divide in an uncontrolled way. The Cell Cycle The Cell Cycle Go is modulated by: Mitogens, stimulate cell division, mostly by removing intracellular negative feedback controls that block progress through the cell cycle. Growth factors, which stimulate cell growth by promoting the synthesis of proteins and other macromolecules and by inhibiting their degradation. Survival factors, which promote cell survival by suppressing apoptosis. Resting phase or cell quiescence (heart/neuron) The Cell Cycle Go is modulated by: ALK -1 EGFR KRAS These are tyrosine kinases Regulation of The Cell Cycle Most receptors for growth factors are tyrosine kinases Al Pacino says: A tyrosine kinase? WHAT THE &%$* IS A TYROSINE KINASE ?! Regulation of The Cell Cycle Most receptors for growth factors are tyrosine kinases • Discovered in 1982 • Receptor for epidermal growth factor (EGF) • When activated, transfers a phosphate group from ATP to selected intracellular tyrosine side chains. • These phosphorylated domains are recognised by intracellular proteins and start a signal cascade. Phase 1: Extracellular signal Phase 2: Intracellular signal cascade Phase 3: Profit. EGFR: Epidermal Growth Factor Receptor Involved in growth; cell proliferation; differentiation and survival Family of four tyrosine kinase receptors • HER-1 (ErbB-1) • HER-2/neu (ErbB-2) • HER-3 (ErbB-3) • HER-4 (ErbB-4) EGFR: Epidermal Growth Factor Receptor A transmembrane cell signalling receptor with four distinct domains: EGF binding site Plasma membrane Tyr Tyr Tyr Tyrosine kinase Tyr Tyr Cytoplasmic tail EGFR: Epidermal Growth Factor Receptor How does it function? Epidermal growth factor (EGF) binds to its receptor (EGFR) on the cell membrane Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr EGFR: Epidermal Growth Factor Receptor How does it function? Homo- and hetero-dimerization of the transmembrane region and autophosphorylation of tyrosine kinase molecules. Signal cascade pathway activated (e.g.MAPK) leading to DNA synthesis and cell replication ATP ADP P P P P P Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr P P P P P EGFR: Epidermal Growth Factor Receptor EGFR RAS GDP Transcription Grb SOS RAS GTP MYC RAF MEK MNK CREB MAPKKK MAPKK MAPK Kirsten rat sarcoma viral oncogene homolog KRAS = Kirsten rat sarcoma viral oncogene homolog KRAS is a molecular switch. KRAS recruits and activates the proteins required in growth factor receptors, e.g.: B-RAF (a member of the MAPK pathway) All this preparation is ignored BRAF initiates the whole signalling cascade at this point Also known to play a role in the Warburg effect of malignant tumours. BRAF was here.. ALK-1: Anaplastic lymphoma kinase Adenocarcinoma of the lung responsible for 3-5% of non-small cell lung cancer ALK-1 is: • the result of a inversion fusion gene mutation on 2q • ALK and EML1 change position • ALK fuses to EML4 • Produces a chimeric fusion protein with constitutive ALK1 action. • Promotes and maintains malignant behaviour. • Almost mutually exclusive with EGFR or KRAS TYROSINE KINASE TAKE HOME MESSAGE • Cell signalling is a complicated process involving many interlocking parts • One solitary change can upset the whole cascade. • Molecular biology is never as simple as it appears!
