Cbl in Regulation of Growth Factor Receptor Endocytosis and Actin Dynamics

Proteins belonging to the Cbl family are multidomain scaffolds that participate in numerous processes, assembling signaling complexes and mediating attachment of ubiquitin to receptor and non-receptor tyrosine kinases.We characterized a novel role for Cbl and Cbl-b in ligand-dependent internalization of growth factor receptors. Upon stimulation with epidermal growth factor (EGF), Cbl proteins associate with EGF receptor, become phosphorylated, and bind to the three SH3 domains of CIN85, which brings endophilins to the complex with active receptors. Endophilins can induce internalization of the plasma membrane, contributing to formation of clathrin-coated pits. We identified a minimal binding domain for CIN85 in the carboxyl termini of Cbl/Cbl-b and observed constitutive association between CIN85, Cbl/Cbl-b and oncogenically stimulated receptor tyrosine kinases. In addition to functioning as a ubiquitin ligase, Cbl forms a complex with CIN85 and endophilin, which is required for efficient endocytosis and downregulation of membrane receptors.In EGF stimulated cells, we observed inducible modification of CIN85 and related CMS proteins by attachment of a single ubiquitin molecule. Monoubiquitination of CIN85 was mediated by the RING finger and dependent on the carboxyl terminal part of Cbl/Cbl-b, and demanded an intact carboxyl terminus of CIN85. Prolonged stimulation with EGF induced concomitant degradation of EGF receptors, Cbl, and monoubiquitinated forms of CIN85 in lysosomes.Cbl regulates cytoskeletal processes in a variety of cell systems…


The Cbl protooncogene
Cbl protein family
Cbl as a tyrosine kinase substrate
Cbl as a scaffolding protein
PTB domain
RING finger
Proline-rich motifs
Phosphoserine motifs
Leucine zipper
Cbl as a ubiquitin ligase
Cbl-deficient mice
Oncogenic Cbl forms
Cbl regulates RTKs signaling
Receptor activation and signal transduction
Ligand-induced endocytosis
Ubiquitin-dependent endosomal sorting
Therapeutic approaches
Cbl regulates actin dynamics
Cbl, CAP and glucose uptake (adipocytes)
Cbl proteins and antigen receptor clustering (T cells)
Cbl, Src and osteoclast function
Cbl/Cbl-b, CIN85 and endophilins negatively regulate RTKs
(Papers I and II)
Mono-ubiquitination of CIN85 is involved in endocytosis and
degradation of the EGFR (Paper III)
SH3P2 participates in Cbl-mediated regulation of actin dynamics
(Paper IV)

Author: Szymkiewicz, Iwona

Source: Uppsala University Library

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