Signaling and receptor-mediated endocytosis

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PROBLEMS & OUTSTANDING QUESTIONS

Cell-surface 'receptors' are involved in transporting cargo from the outside of the cell to the inside. These 'receptors' bind a specific target and deliver their cargo into the cell via endocytosis.

* Q: 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?


NB: The current definition of 'receptor-mediated endocytosis' just seems to cover the initial internalization of the receptor, and not the endosomal sorting events further downstream. This is important if we are considering which endocytosis events the signaling events are controlling.


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.


For a diagram, see [[2]]


' EGFR internalization: a case study''

Many signaling receptors undergo rapid endocytosis following ligand-induced activation (PMID 17662591): the EGFR is one such example. (PMID 14618253).

  • non-ligand bound EGF-receptors are constitutively internalized and recycled back to the cell surface.
  • EGF-induced dimierization of the EGFR generates a dimeric motif on the receptors cytoplasmic tail. which results in efficient binding of the adaptor protein AP2. AP2 thereby links the receptor to be endocytosed with the endocytic machinery. Thereby, activated EGFRs are efficiently internalized into the early endosomal system.
  • Not only internalization but also transport and sorting of the EGFR within the endosomal system appears to be controlled by EGFR sginaling events.
  • TGFalpha dissociates from the EGFR upon endocytosis.
  • EGFR does NOT dissociate from the EGFR upon endocytosis, so signaling activity is preserved in endosomes.
  • Sorting of activated EGFRs into MVBs and subsequent delivery to lysosomes may disconnect the receptor from its cytoplasmic downstream signaling molecules, thereby regulating signal duration.


  • RTKs signal from endosomes.
    • Therefore signaling from the EGFR is not terminated upon internalization.
    • Several RTKs use endosomes as a compartment for the activation of specialized signaling complexes.


SIGNALING REGULATES ENDOCYTOSIS

PMID 17662591

  • regulation of endocytosis by kinases
    • Many kinases modulate endocytic proceses; most of the kinases function as downstream modulators in conventional receptor-linked signaling pathways.
  • regulation of endocytosis by receptors
    • EGFR is reported to promote coated pit formation, inhibit early to late endosome maturation, and promote involution of MVB.
    • It's possible that activated receptors organize their own endocytosis. (EGFR is able to activate its own internalization by modulating the activity of the endocytic machinery: PMID 15084302)

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 (The odd couple: signal transduction and endocytosis)
  • PMID 17662591 (Signaling on the endocytic pathway)
  • PMID 15084302 (Endocytosis: signaling from endocytic membranes to the nucleus)
  • PMID 12827279 (LDL receptor relatives at the crossroad of endocytosis and signaling)
  • PMID 12671190 (Integration of endocytosis and signal transduction by lipoprotein receptors)
  • PMID 19401589 (Nontraditional signaling mechanisms of lipoprotein receptors)


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


CARGO RECEPTORS (JUNE 2011)

Read the discussion on how cargo/transport receptors should be handled.


CHANGES DONE

Created the following terms for regulation of signaling events by receptor-mediated endocytosis (revision 1.2057, June 2011).

 regulation of signal transduction by receptor internalization ; GO:0038009
 positive regulation of signal transduction by receptor internalization ; GO:0038010
 positive regulation of signal transduction by receptor internalization ; GO:0038011
 negative regulation of Wnt receptor signaling pathway by Wnt receptor internalization ; GO:0038012
 positive regulation of Wnt receptor signaling pathway by Wnt receptor internalization ; GO:0038013
 negative regulation of insulin receptor signaling pathway by insulin receptor internalization ; GO:0038014
 positive regulation of insulin receptor signaling pathway by insulin receptor internalization ; GO:0038015
 insulin receptor internalization ; GO:0038016
 Wnt receptor internalization ; GO:0038017
 Wnt receptor catabolic process ; GO:0038018
 Wnt receptor recycling ; GO:0038019
 insulin receptor recycling ; GO:0038020


Created the following term via TermGenie (July 1st):

 endosomal signal transduction ; GO:2000803
 def: "The process in which a signal is passed on to downstream components located at the endosome. Endosomes can provide important intracellular signaling platforms and provide spatial and temporal control over signal transduction."    [PMID:17662591, PMID: 15084302, GOC:bf, GOC:signaling]
 synonym: endosome-based signaling [PMID:17662591]
 synonym: signaling from endosomes [PMID:17662591]