Normal and pathological activation of receptor protein-tyrosine kinases: A case of molecular mimicry, a taste for salt, and why do we give a Shc

Signaling downstream of receptor protein-tyrosine kinases (RPTKs) controls a number of important processes, including proliferation, cell survival, differentiation, and migration. Upon ligand binding, RPTKs autophosphorylate on one or more tyrosine residues. These phosphorylation sites act either to regulate the kinase activity of the receptor or function as binding sites for cellular signaling proteins. It is through the interactions with these proteins that receptors turn on downstream signaling pathways. One such signaling protein is the cytoplasmic adaptor protein Shc. It is thought that the sole function of Shc is to link activated RPTKs to another adaptor protein, Grb2. Utilizing the NGF receptor, we provide evidence that Shc does more than just mediate the interaction of Grb2 with activated RPTKs.; Mammalian cells are able to detect hyperosmotic conditions in the extracellular environment. However, the receptors that are affected directly by osmotic stress remain to be identified. It has been suggested that RPTKs are activated as a consequence of hyperosmotic shock. We have shown that hyperosmotic shock inhibits signal transduction by RPTKs. Ras, an important effector of RPTK signaling, is activated under hyperosmotic conditions. However, activation of Raf, immediately downstream of Ras, is strongly reduced. This suggests that there is an essential step during Raf activation that is sensitive to osmotic stress.; Listeria monocytogenes utilizes its surface protein internalin B (InlB) to mediate invasion of mammalian cells through the activation of the HGF receptor. Direct comparison of the signaling induced by HGF and InlB shows that both ligands turn on the HGF receptor to similar levels, but InlB appears to be a much better activator of the Ras-MAP kinase pathway. This suggests that InlB induces signaling in a manner that is distinct from HGF. Analysis of a series of InlB-deletion mutants demonstrated that the LRR region is sufficient for HGF receptor binding. The C-terminal GW domain and the B-repeat are important for maximal receptor activation and activation of the RasMAP kinase pathway, respectively. We also provide evidence that the GW domains contribute to HGF receptor activation by binding to heparin.