Cbl signaling networks in the regulation of cell function

Abstract

Cbl proteins control multiple cellular processes by acting as ubiquitin ligases and multifunctional adaptor molecules. They are involved in the control of cell proliferation, differentiation and cell morphology, as well as in pathologies such as autoimmune diseases, inflammation and cancer. Here we review recent advances in understanding the role of Cbl and the importance of a growing repertoire of Cbl-interacting proteins in the regulation of signaling pathways triggered by growth factors, antigens, cell adhesion, cytokines and hormones. We also address key issues of the nature of proteins that bind Cbl in particular cells, where they are located, and how they are altered or traffic within cells upon stimulation. It is becoming obvious that temporal and spatial changes in Cbl signaling networks are essential for the control of physiological processes in a variety of cells and organs and that their deregulation can result in the development of human diseases.

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

“…It is well known that the inhibition of PI3K/Akt activation by Cbl-b is dependent on a functional Cbl RING finger (18)(19)(20)(21)(22). Based on our research, this mutation could be responsible for the deregulation of proliferation of AML blasts and the promotion of resistance to ATO or chemotherapeutic agents.…”

“…The E3 ubiquitin ligase Cbl-b functions as a negative regulator of PI3K activation. Ubiquitination of the p85-regulatory subunit of PI3K by Cbl-b affects its phosphorylation of downstream substrates, including Akt (18)(19)(20)(21)(22). T lymphocytes from Cbl-b-deficient mice show enhanced proliferation and cytokine production in response to the triggering of T-cell receptors (22,23).…”

“…The combination of small molecule inhibitors of the PI3K/Akt pathway and standard chemotherapy has been successful in attenuating chemotherapeutic resistance, but further study of the molecules modulating PI3K/ Akt signaling is necessary. E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in several functions of T lymphocytes and osteoblasts (18)(19)(20)(21)(22). Cbl-b-deficient T lymphocytes show enhanced proliferation (22)(23)(24).…”

Molecular Characterization of Ring Finger Protein 11

“…Ring finger -containing proteins, such as CBL, MDM2, and ROC1, are involved in the ubiquitin-mediated proteolysis pathway (13,(29)(30)(31)(32)(33)(34). This pathway has been implicated as a mechanism behind cancer development.…”

SH3P2 in complex with Cbl and Src

“…The identification of the proto-oncogene Casitas B-lineage lymphoma (Cbl) has been a starting point for many exciting discoveries that led to better understanding of how various signaling pathways regulate biological responses in living cells [1]. Thanks to its complex structure Cbl associates with receptor and non-receptor tyrosine kinases, mediates their ubiquitination, and serves as a scaffolding molecule for many signaling proteins.…”