Ch 5: Growth Factors, Receptors, and Cancer
Because a multicellular organism can exist only if its individual cells work in a coordinated fashion, the problems of cell-to-cell communication were solved by the time the first metazoa arose. Deregulation of such cell signaling is central to the formation of cancer.
Src provided the first insight into how oncoproteins function when it was found to operate as a protein kinase--an enzyme that transfers phosphates from ATP to other proteins in the cell. Since multiple distinct protein substrates could be phosphorylated and since each of these could affect its own set of downstream targets, this explained how Sr could act pleiotropically to yield the numerous biological changes observed in RSV-transformed cells.
Most protein kinases phosphorylate threonine or serine residues, but Sc functions as a tyrosine kinase: it attaches phosphates to tyrosine residues of its protein substrate. Tyrosine phosphorylation is favored by mitogenic signaling pathways.
Study of tyrosine kinase receptors (RTKs), such as the epidermal growth factor receptor (EGF-R), elucidated how they transduce signals from a cell's exterior into its cytoplasm. Binding of growth factor ligand to the N-terminal ectodomain of a cognate receptor induces dimerization of the receptor. This activates each monomer's kinase to phosphorylate its partner's tyrosines on the partner's C-terminal cytoplasmic domain. The resulting phosphotyrosines then enable emission of mitogenic signals to downstream target proteins within the cell.
The dimerization model explains how over-expression of growth factor receptors favors cancer formation: when over-expressed, the high numbers of receptor molecules collide frequently as they move around the plane of the plasma membrane, resulting in dimerization, transphosphorylation, receptor activation, and emission of mitogenic signals.
Mutations affecting any of the three RTK domains may create ligand-independent firing. An EGF-R with a truncated ectodomain cannot recognize its ligand but nonetheless emits growth-stimulatory signals in a constitutive faSHIon. Gene fusion events may create receptors that signal unremittingly by virtue of their ectodomains becoming fused with proteins that are naturally prone to dimerize or oligomerize. Amino acid substitutions or deletions in the transmembrane and cytoplasmic domains of receptors are also found in some cancers.
Another mechanism for cell transformation is exemplified by the Sis oncoprotein of simian sarcoma virus. The virus forces an infected cell to release copious amounts of a PDGF-like protein, which attaches to the PDGF receptors of the same cell. 'This creates an autocrine signaling loop in which a cell manufactures a mitogen to which it can also respond.
Other classes of receptors besides RTKs are important in cancer:
Cytokine receptors lack tyrosine kinase domains and rely on noncovalently associated JAK tyrosine kinases for signaling instead of covalently associated TK domains.
Receptors for TGF-B have cytoplasmic kinase domains that phosphorylate serine and threonine rather than tyrosine residues.
Notch receptor forgoes activation by phosphorylation and instead relies on proteases to liberate a cytoplasmic domain fragment that migrates to the nucleus, where it regulates gene expression.
The Patched-Smoothened system relies on one transmembrane protein controlling another, which in turn controls a transcriptional regulator.
Binding of canonical Wnt factors to a Frizzled receptor triggers a cascade of steps that prevents a cytoplasmic kinase from tagging B-catenin for destruction.
G-protein-coupled receptors (GPCRs) induce heterotrimeric G-proteins to flip from an inactive GDP bound state to a signaling GTP-bound state.
Integrins constitute a large family of heterodimeric transmembrane cell surface receptors, almost all of which have CM components as their ligands.
Upon ligand binding, integrins form focal adhesions that link their cytoplasmic domains to the actin cytoskeleton. Integrins pass information both into and out of the cell.
While Ras proteins seemed to be part of a signaling cascade lying downstream of RTKs, the biochemical mechanisms connecting them were obscure, since the tyrosine kinase activity of RTKs had no apparent connection with the GTPase-bearing Ras protein.