CD2-associated Protein (CD2AP) Enhances Casitas B Lineage Lymphoma-3/c (Cbl-3/c)-mediated Ret Isoform-specific Ubiquitination and Degradation via Its Amino-terminal Src Homology 3 Domains

Calco, Gina N.; Stephens, Olivia R.; Donahue, Laura; Tsui, Cynthia C.; Pierchala, Brian A.

doi:10.1074/jbc.m113.537878

Cited by 11 publications

(10 citation statements)

References 40 publications

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“…Ubiquitylation of RTKs can promote endocytosis, as well as target receptors for degradation or recycling (Haglund and Dikic, 2012). Consistent with previous studies (Calco et al, 2014;Kales et al, 2014;Scott et al, 2005), we have shown that the RET9 and RET51 isoforms are ubiquitylated upon GDNF stimulation. Our data, which focus on ubiquitylation of wild-type RET isoforms rather than oncogenic activated mutants, allow us to evaluate early events in response to GDNF-mediated RET ubiquitylation and suggest there may be differences in these processes between RET9 and RET51.…”

Section: Discussionsupporting

confidence: 92%

“…Cbl-b CBL family members have also been identified in some cell types (Calco et al, 2014;Kales et al, 2014;Pierchala et al, 2006), perhaps suggesting that other members of this family could compensate for CBL depletion but not GRB2 loss in RET51 ubiquitylation and internalization in SH-SY5Y. Together, our data implicate a GRB2-CBL complex in RET51 internalization in SH-SY5Y cells, consistent with recent studies demonstrating that depletion of multiple CBL family members was not sufficient to abrogate EGFR internalization but that GRB2 KD blocked receptor endocytosis (Fortian et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…The casitas B-lineage lymphoma (CBL) family are prominent contributors to RTK ubiquitylation (Mohapatra et al, 2013), but other E3 ligases, such as the NEDD4 (neural precursor cell expressed, developmentally downregulated) family have cell-type-specific regulatory roles in ubiquitylation of specific RTKs (Boase and Kumar, 2015). Previous studies have shown that RET recruits CBL family members via interactions with adaptor proteins such as GRB2, but that RET isoforms may differ in their ability to recruit and be ubiquitylated by CBL family members (Calco et al, 2014;Carniti et al, 2003;Kales et al, 2014;Scott et al, 2005). The roles of other ubiquitin ligases in RET ubiquitylation have not been well characterized.…”

Section: Introductionmentioning

confidence: 99%

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Differential recruitment of E3 ubiquitin ligase complexes regulates RET isoform internalization

Hyndman

Crupi

Peng

et al. 2017

Journal of Cell Science

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The RET receptor tyrosine kinase is implicated in normal development and cancer. RET is expressed as two isoforms, RET9 and RET51, with unique C-terminal tail sequences that recruit distinct protein complexes to mediate signals. Upon activation, RET isoforms are internalized with distinct kinetics, suggesting differences in regulation. Here, we demonstrate that RET9 and RET51 differ in their abilities to recruit E3 ubiquitin ligases to their unique C-termini. RET51, but not RET9, interacts with, and is ubiquitylated by CBL, which is recruited through interactions with the GRB2 adaptor protein. RET51 internalization was not affected by CBL knockout but was delayed in GRB2-depleted cells. In contrast, RET9 ubiquitylation requires phosphorylation-dependent changes in accessibility of key RET9 C-terminal binding motifs that facilitate interactions with multiple adaptor proteins, including GRB10 and SHANK2, to recruit the NEDD4 ubiquitin ligase. We showed that NEDD4-mediated ubiquitylation is required for RET9 localization to clathrin-coated pits and subsequent internalization. Our data establish differences in the mechanisms of RET9 and RET51 ubiquitylation and internalization that may influence the strength and duration of RET isoform signals and cellular outputs.This article has an associated First Person interview with the first authors of the paper.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential recruitment of E3 ubiquitin ligase complexes regulates RET isoform internalization

Hyndman

Crupi

Peng

et al. 2017

Journal of Cell Science

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“…The interaction between CBLC and EGFR leads to the attenuation of MAP kinase signalling [ 22 ]. Likewise, CBLC enhances ubiquitylation and degradation of the oncoprotein RET [ 26 , 27 ]. CBLC has also been shown to form a complex with HIC5 (Hydrogen peroxide-inducible clone 5) and the heat shock protein HSP27.…”

Section: Discussionmentioning

confidence: 99%

Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity

et al. 2015

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Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors.

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“…The protein stability of Ret9 and Ret51 has been reported to be different, but further experiments are needed to clarify this issue in DA neurons [159][160][161][162]. Members of the Cbl family of E3 ubiquitin ligases can ubiquitinate Ret at Lys 1060 and Lys 1107 [160,163,164] and thereby mark Ret for lysosomal [160,162] and/or proteasomal degradation [161,165].…”

Section: Function Of the Receptor Tyrosine Kinase Ret In The Midbrainmentioning

confidence: 99%

GDNF–Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease

Kramer

Liss²

2015

FEBS Letters

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a b s t r a c tGlial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate http://dx.doi.org/10.1016/j.febslet.2015.11.006 0014-5793/Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.Abbreviations: 6-OHDA, 6-hydroxy-dopamine; Akt, PKB, protein kinase B, serine/threonine-specific protein kinase; BDNF, brain derived neurotrophic factor; CaMKIIb, calcium-calmodulin-dependent protein kinase II b isoform; cAMP, 3 0 ,5 0 -cyclic adenosine monophosphate; catecholamine, monoamine, neurotransmitter type including dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline); CCCP, carbonyl cyanide m-chlorophenyl hydrazone; Cdc42, cell division control protein 42 homolog, a plasma membrane-associated small GTPase of the Rho family; COMT, catechol-O-methyltransferase; CoREST, co-repressor for element-1-silencing transcription factor, a chromatin-modifying corepressor complex that acts with REST (repressor for element-1 silencing transcription factor) complex; GABA, c-aminobutyric acid, inhibitory neurotransmitter in mammalian central nervous system; GTPase, cycles between an active GTP-bound and an inactive GDP-bound state; DA, dopaminergic; DAT, dopamine transporter; DJ-1, deglycase, oxidative stress sensor and redox-sensitive chaperone and protease; DOK1/4/5/6, docking proteins, have a PH and SH3 domain; EGFP, enhanced green fluorescent protein; EGR1, early growth response protein 1, Zif268 (zinc finger protein 225), NGFI-A (nerve growth factor-induced protein A), is a zinc finger transcription factor; Enigma, adaptor protein of the PDZ-LIM family; ER, endoplasmatic reticulum; ERK, extracellular-signal-regulated kinases, classical MAPKs; FosB/DFosB, FBJ murine osteosarcoma viral oncogene homolog B, a transcription factor with a truncated D form; FRS2, fibroblast growth factor receptor substrate 2, adaptor protein; GAP1/2, GTPase-activating proteins 1 and 2; GDNF, glia cell line-derived neurotrophic factor; GFLs, GDNF family of ligands; GFRa, GDNF family receptor a; GPI, glycosylphosphatidylinositol; GRB2/7/10, growth factor receptor-bound protein 2, 7 and 10, adaptor proteins; gsk3b, glycogen synthase kinase 3b; HIF-1a, hypoxia-inducible factor-1alpha; IRS1/2, insulin receptor substrate 1, adaptor protein, contains a PTB and PH domain; JNK, c-Jun N-terminal kinases, members of the MAPK family of proteins; Kv4.3 and KChip3, subunits of the Ca 2+ -sensitive, voltage gated A-type K+ channel; LIM, (acronym combining the first letters of three proteins -Lin11, Isl-1 and Mec-3 -that have this common domain) protein interaction domain of two contiguous zin...

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CD2-associated Protein (CD2AP) Enhances Casitas B Lineage Lymphoma-3/c (Cbl-3/c)-mediated Ret Isoform-specific Ubiquitination and Degradation via Its Amino-terminal Src Homology 3 Domains

Cited by 11 publications

References 40 publications

Differential recruitment of E3 ubiquitin ligase complexes regulates RET isoform internalization

Differential recruitment of E3 ubiquitin ligase complexes regulates RET isoform internalization

Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity

GDNF–Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease

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