P75 receptor

Etanercept is a fully human dimeric fusion protein composed of human TNF-a p75 receptor fused to the Fc portion of human IgG 1.41 It acts as a tumor necrosis factor-a (TNF-a) inhibitor by binding to and inactivating TNF-a, thus preventing interactions with its cell surface receptors.41 This agent is useful for chronic moderate to severe plaque psoriasis and for psoriatic... 

Cholinergic neurons in the basal forebrain and medial septum selectively express the low affinity (p75) receptor for nerve growth factor which allows them... 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Etanercept is a recombinant fusion protein consisting of two soluble TNF p75 receptor moieties linked to the Fc portion of human IgG (Figure 36-4) it binds TNF- molecules and also inhibits lymphotoxin-a. 

Franklin CM. Clinical experience with soluble TNF p75 receptor in rheumantoid arthritis. Semin Arthitis Rheum 1999 29 171-181. 

Etanercept is a recombinant fusion protein consisting of two soluble TNF p75 receptor moieties... 

SCs via activation of NF-kB. Although mechanisms behind p75-mecliated death of SCs are poorly understood, Yeiser et al. (2004) have shown that NGF signaling through the p75 receptor is deficient in TRAF-6 (-/-) mice and that NGF is unable to kill TRAF-6 (-/-) SCs. In addition, TGFp is also known to cause apoptosis of SCs via INK in culture (lessen and Mirsky, 2005). 

Yeiser EC, Rutkoski NJ, Naito A, Inoue J, Caifer BD (2004) Neru o-tr ophin signaling tlri ougli tire p75 receptor is deficient in tr af6-/— mice. J Neui osci 24 10521—10529. 

The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6. All neurotrophins are capable of binding to the p75 receptor each neurotrophin also binds to a specific Trk receptor. Trk is the receptor for NGF TrkB is the receptor for BDNF and NT-4, while TrkC is the receptor for NT-3. Neurotrophins secreted by cells protect neurons from apoptosis (Korsching, 1993 Lewin and Barde, 1996). Similarly, ciliary neurotrophic factor (CNTF), a structurally related type I cytokine and GDNF, structurally related to TGF-[3, each constitute a sub-family of neurotrophic factors. 

Meldolessi J, Sciorad C, Clemeird E (2000) The p75 receptor First hrsights iirto dre ti asirducdoir mechaursms leadirrg to eidrer deadr or sur vival. TiPS 21 242—243. 

Williams MA, Turchan J, Lu Y, Nath A, Drachman DB (2005) Protection of human cerebral neurons from neurodegenerahve insults by gene delivery of soluble tumor necrosis factor p75 receptor. Exp Brain Res 165 383—391. 

Meldolessi 1, Sciorati C, dementi E (2000) The p75 receptor First insights into the trasnduction mechanisms leading to either death or survival. TiPS 21 242-243. 

Yamashita, T, Higuchi, H, Tohyama, M, The p75 receptor transduces the signal from myehn-associated glycoprotein to Rho, J. Cell. Biol, 157, 565-570, 2002. 

The cross-reactivities (amino acid sequence homology between human and mouse) for different TNFs are TNFa (79%) and TNFP (74%). There is a significant cross-species reactivity. However, human TNF binds to the mouse p55 receptor but not to the mouse p75 receptor. Mouse TNF binds to both human receptors. 

Activated cells shed their TNF receptors and soluble forms of both the human p55 and p75 receptors they have been found in serum of cancer patients and in urine. They may act as competitive inhibitors of the ceU surface receptors. These are soluble receptors, as many cytokines... 

Greene, L. A. and Kaplan, D. R., Early events in neurotrophin signalling via Trk and p75 receptors, Curr. Opin. Cell Biol., 5, 579, 1995. 

Phase II p75 receptor worsened outcome (p <.01) p55 receptor no overall benefit in phase III despite favorable trends in phase II No overall benefit, preliminary report... 

Keywords Neurotrophins Brain derived neurotrophic factor (BDNF) p75 receptor NGF neurotrophin-3 (NT-3) neurotrophin-4/5 (NT-4)... 

It is therefore not correct to refer to p75 and Trk receptors as low and high affinity receptors, since TrkA and TrkB displayed predominantly low affinity values (Hempstead et al., 1991 Dechant et al., 1993) and p75 receptors can exist in a high affinity state (Dechant and Barde, 1997). It is more correct to use the terms high and low affinity to refer to binding sites. 

After binding neurotrophins, the ligand-receptor complex is internalized and retrogradely transported in the axon to the cell body (Distefano et al., 1992). Both Trk and p75 receptors play a role in the retrograde transport of neurotrophins. For example, in the isthmo-optic nucleus, BDNF is taken up at the axon terminal and transported to the cell body by both p75 and TrkB receptors (von Bartheld et al., 1995). 

Direct interactions between p75 and Trk receptors have been difficult to document biochemically. However, im-munoprecipitation experiments carried out in crosslinked spinal cord and brain tissues with I-NGF suggest that an association between the TrkA and p75 may take place (Huber and Chao, 1995). Photobleaching experiments following a fluorescently tagged p75 receptor have also revealed a potential physical interaction with TrkA receptors (Wolf et al., 1995). 

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