[Cbl--a polyfunctional regulator of cellular processes].
C-Cb1 protein is a protooncogene product that was initially identified as part of a murine retrovirus transforming protein. C-Cb1 is ubiquitously expressed in cells of different origin. A number of isoforms subsequently identified in vertebrates and invertebrates allows to consider the existence of a family of Cb1 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.). Cb1 proteins possess also multiple tyrosine, residues, which undergo phosphorylation upon stimulation of several surface receptors. These properties permit Cb1 to take part in many protein-protein interactions as an adaptor, which forms multimolecular signaling complexes, and coordinates the activity of its components. C-Cb1 and its mutant transforming forms can act as both positive and negative regulators of many signaling pathways. Negative action of C-Cb1 on signals stimulated by receptor tyrosine kinases is thought to result from accelerated receptor degradation caused by Cb1. This ability is attributed mostly to ubiquitin-ligase activity of Cb1 proteins, since the latest research evidence suggests that ubiquitination may be a signal of not only proteasomal, but also lysosomal degradation. Thus, Cb1 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 Cb1 functions, interrelations between these functions, physiological significance of Cb1-mediated interactions, and the place of Cb1 proteins in signaling coordinating still remain obscure. In the present review, an attempt is made to summarize the recent data, with special reference to Cb1 functioning as a regulator of tyrosine kinase receptor endocytosis.
Melikova
M S
MS
Institute of Cytology RAS, St. Petersburg.
Filatova
M M
MM
Kornilova
E S
ES
D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D000818:Animals; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
D033942:Adaptor Proteins, Vesicular Transport; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D020794:Receptor Protein-Tyrosine Kinases; C067419:CBL protein, human