Glial Cell Line-Derived Neurotrophic Factor-Dependent Recruitment of Ret into Lipid Rafts Enhances Signaling by Partitioning Ret from Proteasome-Dependent Degradation

Pierchala, Brian A.; Milbrandt, Jeffrey; Johnson, Eugene M.

doi:10.1523/jneurosci.3420-05.2006

Cited by 88 publications

(83 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, translocation into lipid rafts protects Ret from ubiquitination and consequential targeting for degradation (Pierchala et al 2006). These data suggest that lipid rafts promote receptor longevity, such that ubiquitin ligases and the cellular machinery that regulate ubiquitination may have restricted access to lipid rafts.…”

Section: Function Of Lipid Rafts In Neural Cellsmentioning

confidence: 87%

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Romanelli

Wood²

2008

Journal of Neurochemistry

View full text Add to dashboard Cite

The trafficking of receptor tyrosine kinases (RTKs) to distinct subcellular locations is essential for the specificity and fidelity of signal transduction and biological responses. This is particularly important in the PNS and CNS in which RTKs mediate key events in the development and maintenance of neurons and glia through a wide range of neural processes, including survival, proliferation, differentiation, neurite outgrowth, and synaptogenesis. The mechanisms that regulate the targeting of RTKs to their subcellular destinations for appropriate signal transduction, however, are still elusive. In this review, we discuss evidence for the spatial organization of signaling machinery into distinct subcellular compartments, as well as the role for ligand specificity, receptor sorting signals, and lipid raft microdomains in RTK targeting and the resultant cellular responses in neural cells.

show abstract

Section: Function Of Lipid Rafts In Neural Cellsmentioning

confidence: 87%

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Romanelli

Wood²

2008

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Because Ret9 and Ret51 are degraded with markedly different kinetics (Scott et al, 2005;Pierchala et al, 2006), we tested whether there is a difference in the association between Cbl-3 and CD2AP with these Ret isoforms. When Ret9 or Ret51 was coexpressed with CD2AP in HEK293 cells, CD2AP associated with both Ret9 and Ret51 (Fig.…”

Section: Cbl-3 Binds Directly To Both Ret and Cd2apmentioning

confidence: 99%

“…Receptor downregulation, which controls the length of time that downstream signaling cascades are active, can dictate how the target cell responds. After its activation, Ret is rapidly ubiquitinated and degraded (Scott et al, 2005;Pierchala et al, 2006). This degradation pathway is the predominant means of termination of GFL signaling cascades and limits the effectiveness of GFLs as survival signals (Scott et al, 2005;Pierchala et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…After its activation, Ret is rapidly ubiquitinated and degraded (Scott et al, 2005;Pierchala et al, 2006). This degradation pathway is the predominant means of termination of GFL signaling cascades and limits the effectiveness of GFLs as survival signals (Scott et al, 2005;Pierchala et al, 2006). Unlike other RTKs, Ret is degraded mainly by the proteasome, but the molecules required for this process are unknown .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

View full text Add to dashboard Cite

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance. GFLs promote survival and growth via activation of the receptor tyrosine kinase (RTK) Ret. In sympathetic neurons, the duration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with Ret under basal, unstimulated conditions in neurons. After Ret activation by GDNF, CD2AP dissociates. Similarly, the E3-ligase Cbl-3 interacts with unphosphorylated Ret and dissociates from Ret after Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3 acts as a switch that is triggered by CD2AP and oscillates between inhibition and promotion of Ret degradation. Consistent with the hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing. CD2AP and Cbl-3, therefore, constitute a checkpoint that controls the extent of Ret downregulation and, thereby, the sensitivity of neurons to GFLs.

show abstract

“…We have shown previously that, upon ligand activation and autophosphorylation, RET is rapidly poly-ubiquitinated and targeted for degradation (49). Because ectopic FIGURE 6.…”

Section: ⌬E3mentioning

confidence: 99%

Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction

Gabreski

Vaghasia

Novakova

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Rearranged during transfection (RET), a receptor tyrosine kinase that is activated by the glial cell line-derived neurotrophic factor family ligands (GFLs), plays a crucial role in the development and function of the nervous system and additionally is required for kidney development and spermatogenesis. RET encodes a transmembrane receptor that is 20 exons long and produces two known protein isoforms differing in C-terminal amino acid composition, referred to as RET9 and RET51. Studies of human pheochromocytomas identified two additional novel transcripts involving the skipping of exon 3 or exons 3, 4, and 5 and are referred to as RET ⌬E3 and RET ⌬E345 , respec- higher baseline autophosphorylation, specifically on the catalytic tyrosine, Tyr 905 , and also on one of the most important signaling residues, Tyr 1062 . These data provide the first evidence for a physiologic role of these isoforms in RET pathway function.RET is a receptor tyrosine kinase that is critical for kidney morphogenesis, spermatogenesis, and development of the nervous system (1-4). RET is activated by a family of four growth factors known as the glial cell line-derived neurotrophic factor (GDNF) 2 family ligands (GFLs), which includes GDNF, neurturin, artemin, and persephin (1). Each GFL binds to one of four cognate glycosylphosphatidylinositol-anchored co-receptors known as the GDNF family receptor ␣s (GFR␣s) (2, 5). The GFL-GFR␣ complex binds to RET, inducing RET dimerization and subsequent autophosphorylation on multiple tyrosine residues within the intracellular tyrosine kinase domain. This enhances tyrosine kinase activity and initiates the association of adaptor proteins and enzymes that trigger multiple second messenger cascades (6). The presence of two major Ret isoforms, RET9 and RET51, has been extensively described in the literature, and a third isoform, RET43, has also been observed in humans (7-9). Ret is 20 exons long, and Ret9 and Ret51 transcripts differ in alternative splicing of intron 19. Intron 19 in the Ret51 transcript is excised properly, whereas, in the Ret9 transcript, the intron is retained, changing the reading frame and inserting a premature stop codon into the amino acid sequence. This creates a unique nine-amino acid C-terminal sequence for RET9 and a unique 51-amino acid C-terminal sequence for RET51. Interestingly, these two different isoforms display marked differences in their degradation and function (7, 10, 11).Three additional Ret transcripts have been reported in various tumor sources as well as adult human tissues (12). These novel transcripts are a product of exon skipping in the 5Ј region of RET, which encodes for the extracellular domain of the protein. Skipping of exons 3 (RET ⌬E3 ) or exons 3, 4 and 5 (RET ⌬E345) gives rise to transcripts that encode for full-length Ret proteins but with deletions in the extracellular domain, specifically cadherin-like domain 1 (CLD1) or CLD1-3, respectively. These deletions are hypothesized to change the extracellular domain structure as well as binding to GFL-GFR...

show abstract

Glial Cell Line-Derived Neurotrophic Factor-Dependent Recruitment of Ret into Lipid Rafts Enhances Signaling by Partitioning Ret from Proteasome-Dependent Degradation

Cited by 88 publications

References 52 publications

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction

Contact Info

Product

Resources

About