title: Activation of receptor protein-tyrosine kinases from the cytoplasmic compartment.
abstract: It is widely accepted that receptor protein-tyrosine kinases (RTKs) are activated upon dimerization by binding to their extracellular ligands. However, EGF receptor (EGFR) dimerization per se does not require ligand binding. Instead, its cytoplasmic kinase domains have to form characteristic head-to-tail asymmetric dimers to become active, where one 'activator' domain activates the other 'receiver' domain. The non-catalytic, cytoplasmic regions of RTKs, namely the juxtamembrane and carboxy terminal portions, also regulate kinase activity. For instance, the juxtamembrane region of the RTK MuSK inhibits the kinase domain probably together with a cellular factor(s). These findings suggest that RTKs could be activated by cytoplasmic proteins. Indeed, Dok-7 and cytohesin have recently been identified as such activators of MuSK and EGFR, respectively. Given that failure of Dok-7 signaling causes myasthenia, and inhibition of cytohesin signaling reduces the proliferation of EGFR-dependent cancer cells, cytoplasmic activators of RTKs may provide new therapeutic targets.
authors.affiliation: Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. yyamanas@ims.u-tokyo.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamanashi
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D032446:Myoblasts / Q000201:enzymology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009469:Neuromuscular Junction / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: C511692:DOK7 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D020794:Receptor Protein-Tyrosine Kinases