Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl

Sun, Jianmin; Pedersen, Malin; Bengtsson, Susanne; Rönnstrand, Lars

doi:10.1016/j.yexcr.2007.08.021

Cited by 39 publications

(44 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Goh and A. Sorkin mammalian isoforms of Cbl (Cbl-b, Cbl-3, and c-Cbl) bind directly to specific phosphorylated tyrosines in RTKs, and long Cbl species (c-Cbl and Cbl-b) bind EGFR, c-Met, PDGFR-b, stem cell factor receptor (c-kit), and other RTKs indirectly through the SH2 adaptor protein Grb2 (Batzer et al 1994;Peschard et al 2001;Waterman et al 2002;Li et al 2007;Sun et al 2007). The key role of Grb2 in ubiquitination and internalization of RTKs via Cbl has been shown using multiple experimental approaches in mammalian cells (Peschard 2001;Huang and Sorkin 2005;Johannessen 2006;Li 2007).…”

Section: Endocytosis Of Receptor Tyrosine Kinasesmentioning

confidence: 99%

Endocytosis of Receptor Tyrosine Kinases

Goh

Sorkin

2013

Cold Spring Harbor Perspectives in Biology

394

398

View full text Add to dashboard Cite

Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work.F unctional activities of transmembrane proteins, including the large family of RTKs, are controlled by intracellular trafficking. RTKs are synthesized in the endoplasmic reticulum, transported to Golgi apparatus, and then delivered to the plasma membrane. At the cell surface RTKs undergo constitutive endocytosis (internalization) at a rate similar to that of other integral membrane proteins. Constitutive internalization of RTKs is much slower than their constitutive recycling from endosomes back to the cell surface. Therefore, RTKs are accumulated at the cell surface, which allows maximal accessibility to extracellular ligands. The rates of the constitutive internalization, recycling, and degradation determine the half-life of an RTK protein, which varies depending on the nature of the RTK and the cell type, and typically positively correlates with the expression level of the RTK. For example, the turnover rates range from t 1/2 ,

show abstract

Section: Endocytosis Of Receptor Tyrosine Kinasesmentioning

confidence: 99%

Endocytosis of Receptor Tyrosine Kinases

Goh

Sorkin

2013

Cold Spring Harbor Perspectives in Biology

394

398

View full text Add to dashboard Cite

show abstract

“…These include the autoubiquitination of CBLs, the interaction with adaptor molecules that recruit CBL to targets, and proteins that inhibit CBL func tion. For example, EGFR down-regulation by CBL involves the adaptor protein GRB2 (166), and a similar mechanism may function in CBLmediated down-regulation of KIT (167). Sprouty 2 (SPRY2) is a target and an inhibitor of CBL.…”

Section: P53 Pathwaymentioning

confidence: 99%

Degrons in cancer

et al. 2017

View full text Add to dashboard Cite

Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

show abstract

“…Cells stably expressing wild-type or mutant Flt3 were established as previously described (Sun et al, 2007). Silencing of Gab2 in Ba/F3 cells was achieved by electroporation (1500 V, 1500 lF) in a Gene PulserII (Bio-Rad, Hercules, CA, USA) in the presence of 100 nmol/l SMARTpool Gab2-siRNA or scrambled siRNA (Dharmacon, Lafayette, CO, USA) and incubation for another 48 h before experiments were performed.…”

Section: Transient and Stable Transfectionmentioning

confidence: 99%

A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival

et al. 2009

Self Cite

View full text Add to dashboard Cite

SummaryThe haematopoietic growth factor receptor Flt3 has been implicated as major cause of transformation in acute myeloid leukaemia. Intracellular signals mediated by wild-type Flt3 are involved in cell differentiation and survival whereas signalling via the mutant Flt3 ITD (internal tandem duplication) promotes enhanced cell growth. In this study, we identified tyrosines 768, 955 and 969 of Flt3 as phosphorylation sites and mediators of growth factor receptor binding protein 2 (Grb2) interaction, leading to the association of Grb2 associated binder 2 (Gab2) and contributing to proliferation and survival. Ba/F3 cells were transfected with either the wild-type Flt3 or the ITD, with or without a triple mutation of the Grb2 binding sites, and characterised in terms of proliferation and viability. Interestingly, the Flt3 ITD promoted increased survival but after introducing the triple mutation, this phenotype was lost. When looking into different downstream pathways, this effect was mainly caused by decreased phosphoinositide 3-kinase and Stat5 signalling, and the Flt3 ITD carrying the Grb2 binding mutations showed less Akt and Stat5 activation compared to the regular Flt3 ITD receptor. These findings not only reveal novel phosphorylation sites in Flt3 but contribute to the understanding of the molecular mechanism by which Flt3 ITD functions in pathological conditions.

show abstract

Grb2 mediates negative regulation of stem cell factor receptor/c-Kit signaling by recruitment of Cbl

Cited by 39 publications

References 27 publications

Endocytosis of Receptor Tyrosine Kinases

Endocytosis of Receptor Tyrosine Kinases

Degrons in cancer

A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival

Contact Info

Product

Resources

About