Activation of receptor protein-tyrosine kinases from the cytoplasmic compartment

• Published in: Journal of biochemistry (Tokyo) Vol. 151; no. 4; pp. 353 - 359
• Main Authors: Yamanashi, Yuji, Tezuka, Tohru, Yokoyama, Kazumasa
• Format: Journal Article
• Language: English
• Published: England 01.04.2012
• Subjects: Animals; Cytoplasm - enzymology; Cytoplasm - metabolism; Enzyme Activation; Guanine Nucleotide Exchange Factors - metabolism; Humans; Molecular Targeted Therapy; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myasthenia Gravis - drug therapy; Myasthenia Gravis - enzymology; Myasthenia Gravis - genetics; Myoblasts - enzymology; Myoblasts - metabolism; Neoplasms - drug therapy; Neoplasms - enzymology; Neuromuscular Junction - enzymology; Neuromuscular Junction - metabolism; Protein Binding; Receptor Protein-Tyrosine Kinases - metabolism
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvs013

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.