Individual and Combined Effects of TrkA and p75NTR Nerve Growth Factor Receptors

Lad, Shivanand P.; Peterson, Daniel A.; Bradshaw, Ralph A.; Neet, Kenneth E.

doi:10.1074/jbc.m212270200

Cited by 71 publications

(61 citation statements)

References 54 publications

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“…Since neurotrophin signaling represents a complex system in which either Trk receptor homodimers, p75 NTR monomers, or mixed complexes between Trk and p75 NTR receptors can be involved (Dechant 2001;Lad et al 2003;Barker 2004), we made efforts to examine comprehensively all components (ligands and receptors) of the neurotrophin signaling network. The analyses of both fetal and adult testes served to address the two hypothesized functional implications, namely in morphogenesis and spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

The expression of neurotrophins and their receptors in the prenatal and adult human testis: evidence for functions in Leydig cells

Müller¹,

Davidoff

Bargheer

et al. 2006

Histochem Cell Biol

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Previous studies have demonstrated local functions for neurotrophins in the developing and mature testis of rodents. To examine whether these signaling molecules are present and also potentially active in the human testis, we characterized immunohistochemically the expression and cellular localization of the known neurotrophins and their receptors during prenatal testicular development as well as in the adult human testis. Results obtained revealed the presence of nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3 and 4, as well as neurotrophin receptors p75(NTR), TrkA, TrkB, and TrkC during testis morphogenesis. These proteins were also detectable in the adult human testis, and their local expression could be confirmed largely by immunoblot and RT-PCR analyses. Remarkably, the Leydig cells were found to represent the predominant neurotrophin/receptor expression sites within both fetal and adult human testes. Functional assays performed with a mouse tumor Leydig cell line revealed that NGF exposure increases cellular steroid production, indicating a role in differentiation processes. These findings support previously-recognized neuronal characteristics of Leydig cells, provide additional evidence for potential roles of neurotrophins during testis morphogenesis and in the mature testis, and demonstrate for the first time a neurotrophin-induced functional activity in Leydig cells.

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Section: Introductionmentioning

confidence: 99%

The expression of neurotrophins and their receptors in the prenatal and adult human testis: evidence for functions in Leydig cells

Müller¹,

Davidoff

Bargheer

et al. 2006

Histochem Cell Biol

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“…In the stimulating process by neurotrophins, activation of TrkA signaling is sufficient for eliciting neurite outgrowth of PC12 cells, and another NGF receptor, p75 NTR signaling plays a modulatory role in the formation of fine synaptic bouton-like structures (Lad et al, 2003). However,p75 NTR alters the conformation of TrkA to generate high-affinity NGF binding (Esposito et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

p190RhoGAP and Rap-dependent RhoGAP (ARAP3) inactivate RhoA in response to nerve growth factor leading to neurite outgrowth from PC12 cells

et al. 2010

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Rat pheochromocytoma (PC12) cells have been used to investigate neurite outgrowth. Nerve growth factor (NGF) has been well known to induce neurite outgrowth from PC12 cells. RhoA belongs to Ras-related small GTP-binding proteins, which regulate a variety of cellular processes, including cell morphology alteration, actin dynamics, and cell migration. NGF suppressed GTP-RhoA levels after 12 h in PC12 cells and was consistently required for a long time to induce neurite outgrowth. Constitutively active (CA)-RhoA suppressed neurite outgrowth from PC12 cells in response to NGF, whereas dominant-negative (DN)-RhoA stimulated it, suggesting that RhoA inactivation is essential for neurite outgrowth. Here, we investigated the mechanism of RhoA inactivation. DN-p190RhoGAP abrogated neurite outgrowth, whereas wild-type (WT)-p190RhoGAP and WT-Src synergistically stimulated it along with accelerating RhoA inactivation, suggesting that p190RhoGAP, which can be activated by Src, is a major component in inhibiting RhoA in response to NGF in PC12 cells. Contrary to RhoA, Rap1 was activated by NGF, and DN-Rap1 suppressed neurite outgrowth, suggesting that Rap1 is also essential for neurite outgrowth. RhoA was co-immunoprecipitated with Rap1, suggesting that Rap1 interacts with RhoA. Furthermore, a DN-Rap-dependent RhoGAP (ARAP3) prevented RhoA inactivation, abolishing neurite formation from PC12 cells in response to NGF. These results suggest that NGF activates Rap1, which, in turn, up-regulates ARAP3 leading to RhoA inactivation and neurite outgrowth from PC12 cells. Taken together, p190RhoGAP and ARAP3 seem to be two main factors inhibiting RhoA activity during neurite outgrowth in PC12 cells in response to NGF.

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“…The two receptors, Trk and p75 NTR , are structurally unrelated with neurotrophins interacting primarily with the Ig-like C2 (IgGC2) domain of the Trk receptors but with the cysteine-rich domains of the p75 NTR receptor (9)(10)(11). Neurotrophin binding to the Trk receptors transduces positive signals like growth, survival, or differentiation, whereas binding to the p75 NTR ͞Trk heterodimer can transduce positive or negative signals (12)(13)(14)(15)(16). Unlike the Trk receptors that possess signature tyrosine kinase motifs, p75 NTR lacks any intrinsic catalytic activity.…”

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confidence: 99%

Construction of a mutated pro-nerve growth factor resistant to degradation and suitable for biophysical and cellular utilization

Pagadala

Dvorak

Neet

2006

Proc. Natl. Acad. Sci. U.S.A.

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Precursor of nerve growth factor (proNGF) has been found to be proapoptotic in several cell types and mediates its effects by binding to p75 neurotrophin receptor (p75 NTR ) and sortilin. The proNGF molecule is processed by proteases at three dibasic sites found in the pro domain to form mature NGF (termed herein as sites 1, 2, and 3 from the proNGF N terminus). Of these processing sites, site 3, adjacent to the N terminus of mature NGF, was thought to be the major site responsible for processing of proNGF to mature NGF. We found that mutating this major processing site (site 3) resulted in a form of proNGF that was only partially stable. On introducing additional mutations in the pro domain at the other two dibasic sites, we found the stability of proNGF to increase significantly. Here we describe the construction, expression, and purification of this more stable proNGF molecule. The two consecutive basic residues at each of the three sites were mutated to neutral alanine residues. Expression was performed in stably transfected Sf21 insect cells. Purification involved strong cationexchange chromatography and N60 immunoaffinity column chromatography. The construct with all three sites mutated (termed proNGF123) gave all proNGF with no mature NGF and was not cleaved by three proconvertases (furin, PACE-4, and PC-2) known to proteolyze proneurotrophins in vivo. This stable proNGF molecule demonstrated proapoptotic activity on rat pheocytochroma PC12 cells, PC12nnr cells, C6 glioblastoma cells, and RN22 schwannoma cells.p75 receptor ͉ Sf21 stable cell line ͉ Trk receptor ͉ neurotrophin ͉ apoptosis

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Individual and Combined Effects of TrkA and p75NTR Nerve Growth Factor Receptors

Abstract: Neurotrophins transduce their effects by interacting with two types of cell surface receptors, the Trk family of tyrosine kinase receptors and the p75 neurotrophin receptor (p75 NTR ).

Cited by 71 publications

References 54 publications

The expression of neurotrophins and their receptors in the prenatal and adult human testis: evidence for functions in Leydig cells

The expression of neurotrophins and their receptors in the prenatal and adult human testis: evidence for functions in Leydig cells

p190RhoGAP and Rap-dependent RhoGAP (ARAP3) inactivate RhoA in response to nerve growth factor leading to neurite outgrowth from PC12 cells

Construction of a mutated pro-nerve growth factor resistant to degradation and suitable for biophysical and cellular utilization

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