Abstract 4986: Distinct temporal regulation of RET isoform internalization: Roles of clathrin and AP2
Bibliographic record
Abstract
Abstract The RET receptor tyrosine kinase is an important contributor to kidney and enteric nervous system development. In normal development, RET signaling regulates cell proliferation, migration, survival and differentiation, but RET is also implicated in growth and spread of several human cancers. Activating mutations of RET are drivers of inherited and sporadic thyroid cancers, while expression of wildtype RET receptors in breast and pancreatic cancers has been associated with enhanced tumor invasion, metastasis and poor disease prognosis. RET is expressed as two major isoforms, RET9 and RET51, that have unique 9 or 51 amino acid C-terminal tails, respectively. These isoforms induce unique phosphorylation patterns on intracellular tyrosine residues, differentially bind downstream signalling proteins, and possess different intrinsic abilities to cause cellular transformation. We have previously shown that RET isoforms are internalized from the cell surface into endosomal compartments in response to glial cell line derived neurotrophic factor (GDNF) ligand stimulation, but the specific mechanisms of RET trafficking remain to be elucidated. Here, we used total internal reflection fluorescence microscopy to demonstrate that RET internalization occurs through clathrin coated pits (CCPs). Activated RET receptors colocalize with clathrin, but not caveolin, at sites of CCPs. The RET51 isoform is rapidly and robustly recruited to CCPs upon GDNF stimulation, while RET9 recruitment occurs more slowly and is less pronounced. We showed that the clathrin-associated adaptor protein complex 2 (AP2) is important for RET internalization. Our data establish that interactions with the AP2 complex promote RET receptor internalization via clathrin-mediated pathways but that RET9 and RET51 have distinct internalization kinetics that may contribute to the functional differences between RET isoforms which are critical to regulating RET's contribution to tumorigenesis and normal development. These data may also have clinical importance, as they characterize key regulatory events for an important oncogene that may in future indicate biologically relevant targets for therapeutic interventions in RET-associated tumors. Citation Format: Mathieu Joseph François Crupi, Piriya Yoganathan, Leslie N. Bone, Eric Lian, Andrew Fetz, Costin N. Antonescu, Lois M. Mulligan. Distinct temporal regulation of RET isoform internalization: Roles of clathrin and AP2. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4986. doi:10.1158/1538-7445.AM2015-4986
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".