CBL AS A POLYFUNCTIONAL REGULATOR OF CELLULAR PROCESSES
M. S. Melikova, M. M. Filatova, E. S. Kornilova 1
Institute of Cytology RAS, St. Petersburg, Russia;
1 e-mail: lenkor@mail.cytspb.rssi.ru
C-Cbl protein is a protooncogene product that was initially identified as part of a murine retrovirus transforming protein.
C-Cbl is ubiquitously expressed in cells of different origin. A number of isoforms sub-sequently identified in vertebrates and invertebrates
allows to consider the existence of a family of Cbl proteins. These proteins contain a set of sequences providing interactions with a
wide range of receptor and nonreceptor tyrosine kinases and signaling proteins with SH2- and SH3-domains (for example, EGF and PDGF
receptors, Src-kinases, PI-3-kinase p85, Crk, GRB2, Vav, etc.). Cbl proteins possess also multiple tyrosine residues, which undergo
phosphorylation upon stimulation of several surface receptors. These properties permit Cbl to take part in many protein-protein interactions
as an adaptor, which forms multimolecular signaling complexes, and coordinates the activity of its components. C-Cbl and its mutant
transforming forms can act as both positive and negative regulators of many signaling pathways. Negative action of C-Cbl on signals
stimulated by receptor tyrosine kinases is thought to result from accelerated receptor degradation caused by Cbl. This ability is attributed
mostly to ubiquitin-ligase activity of Cbl proteins, since the latest research evidence suggests that ubiquitination may be a signal of not
only proteasomal, but also lysosomal degradation. Thus, Cbl manifests itself as a many-sided protein working both as an adaptor and a
regulator of endocytic trafficking. In spite of numerous studies in this area, the regulation of Cbl functions, interrelations between these
functions, physiological significance of Cbl-mediated interactions, and the place of Cbl proteins in signaling coordinating still remain
obscure. In the present review, an attempt is made to summarize the recent data, with special reference to Cbl functioning as a regulator
of tyrosine kinase receptor endocytosis.
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