Neet, Kenneth E. and Campenot, Robert B. (2001) Receptor Binding, Internalization, and Retrograde Transport Of Neurotrophic Factors. In "Structure and Biology of Neurotrophic Factors", review series in Cell Molec. Life Sci., M. Saarma and U. Arumae, eds. (in press)

ABSTRACT
This review deals with the receptor interactions of neurotrophic factors with a focus on the neurotrophins of the nerve growth factor (NGF) family, the glial cell derived neurotrophic factor (GDNF) family, and the ciliary neurotrophic factor (CNTF) family. The finding of two proteins, p75NTR and Trk, that act as receptors for NGF in neurons generated the discovery of other neurotrophic factors/receptor families and has enhanced the understanding of the development, survival, regeneration, and degeneration of the nervous system. The kinetics of binding, structure of the ligand receptor complex, and the mechanism of retrograde transport of the neurotrophins are discussed in detail and compared to information available on the GDNF and CNTF families. Each neurotrophic factor family, i.e. NGF, GDNF, and CNTF, has a set of receptors with specificity for individual members of the family and a common receptor without member specificity that, in some families, generates the cellular signal and retrograde transport.

22 manuscript pages & 149 references

Figure 1. Receptor binding patterns of three neurotrophic factor families.

(A) The NGF neurotrophin family of NGF, BDNF, NT3, and NT4/5. The Trk receptor extracellular domain consists of two cysteine-rich domains, three leucine rich motifs (LRM), and two IgG-like (IgGL) domains; the intracellular domain is a protein tyrosine kinase (PTK). The common p75NTR receptor has four cysteine repeats in the extracellular domain and one or more intracellular death domains.

(B) The GDNF family of GDNF, NTN, ART, and PSP. The GFRa receptors are membrane attached with a glycosyl inositolphosphate (GPI) anchor. The common cRET receptor has an intracellular protein tyrosine kinase (PTK) domain.

(C) The IL-6/CNTF family of IL-6, CNTF, LIF. The other related cytokines [oncostatin M (OM), granulocyte colony stimulating factor (G-CSF), Interleukin-11 (IL-11), and cardiotrophin-1 (CT-1)] (not shown) utilize the common gp130 receptor subunit but have different co-receptor requirements, some of which are not yet well defined. The gp130 and LIFRb receptor extracellular domains have one IgG-like (IgGL) and five fibronectin III-like (FBN-like) domains; the intracellular domain (ICD) binds STAT and/or JAK. The IL6Ra and CNTFRa receptor extracellular domains have an IgG-like and/or a fibronectin-like domain. CNTFRa is GPI anchored whereas IL6Ra has a transmembrane domain and a small ICD.

(D)inset Composition of the signaling complexes for IL-6, CNTF, and LIF. In all cases, higher order receptor aggregates, i.e. heterotetramers or heterohexamers, may occur with the ligand.