Signaling and receptor-mediated endocytosis

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PROBLEM

Receptors are involved in receptor-mediated endocytosis (eg LDL receptors, vitellogenin receptors). Are these signaling receptors, if all they are doing is resulting in endocytosis of the ligand? Is this any different to a transporter moving its substrate, or an enzyme recognizing its substrate?

For a summary of the problems, see slides 61-64 in the following presentation from the February 2011 signaling workshop.

BACKGROUND

Wikipedia

Clathrin binding to the receptor-ligand complex is mediated by a peptide recognition sequence (Phe-Arg-X-Tyr) in the cytoplasmic domain of the receptor that binds to a specific adaptin. Adaptin in turn binds to individual clathrin molecules.

RELATED SOURCEFORGE ITEM

Tanya's SF item suggests splitting the receptors into those that signal and those that endocytose their substrate:

https://sourceforge.net/tracker/?func=detail&aid=2894756&group_id=36855&atid=440764

RELEVANT PAPERS

The following papers discuss the bi-directional link between signaling and endocytosis: PMID 14618253 PMID 12827279 PMID 17662591 PMID 15084302

They discuss that: 1. Endocytosis can regulate signaling pathways - endocytosis NEGATIVELY REGULATES signaling pathways by reducing the number of receptors at the plasma membrane. - endocytosis POSITIVELY REGULATES signaling pathways by concentrating receptors in endosomes that can act as signaling platforms.

2. Signaling pathways can regulate endocytosis - activated receptors may organize their own endocytosis. - other signaling molecules (intracellular kinases etc) can modulate the endocytic machinery and endosomal sorting

PROPOSAL (JUNE 2011)

-I think we are agreed that RME is not a signaling event, and that the first step doesn't count as signal transduction.

-Internalization of the ligand (and/or receptor) can of course regulate a signaling event as it regulates how much ligand or receptor is available for signaling.

Restricting 'receptor activity ; GO:0004872' to those receptors that signal [2] will create the split of signaling receptors and 'other receptors'.

Q: Do we want a generic 'receptor activity' term in MF? If so, how would it be defined other than 'binding'?

 molecular_function
 --%receptor activity ; GO:NEW
 ----%signaling receptor activity ; GO:0004872
 ----%receptor activity involved in endocytosis ; GO:NEW
 ------%lipoprotein particle receptor activity ; GO:0030228
 ------%vitellogenin receptor activity ; GO:0008196
 
 receptor activity ; GO:NEW
 Combining with an extracellular or intracellular molecule or signal to initiate a change in cell activity.

 signaling receptor activity ; GO:0004872
 Combining with a signal to initiate a change in cell activity. A signal is any variable property or parameter that serves to convey information, and may be a physical entity such as a gene product or small molecule, a photon, or a change in state such as movement or voltage change.
 is_a: signal transducer activity
 synonym: receptor involved in signal transduction
 
 receptor activity involved in endocytosis ; GO:NEW
 Combining with a extracellular molecule or organism on the surface of the cell to mediate internalization of the bound substrate.
 part_of: receptor-mediated endocytosis ; GO:0006898
 synonym: endocytotic receptor activity