Tropomyosin receptor kinase A

Last updated
NTRK1
PBB Protein NTRK1 image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NTRK1 , MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA, neurotrophic receptor tyrosine kinase 1
External IDs OMIM: 191315 MGI: 97383 HomoloGene: 1898 GeneCards: NTRK1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002529
NM_001007792
NM_001012331

NM_001033124

RefSeq (protein)

NP_001007793
NP_001012331
NP_002520

NP_001028296

Location (UCSC) Chr 1: 156.82 – 156.88 Mb Chr 3: 87.69 – 87.7 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tropomyosin receptor kinase A (TrkA), [5] also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene. [6]

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself (autophosphorylation) and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain with anhidrosis, self-mutilating behaviors, intellectual disability and/or cognitive impairment and certain cancers. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [7]

Function and Interaction with NGF

TrkA is the high affinity catalytic receptor for the neurotrophin, Nerve Growth Factor, or "NGF". As a kinase, TrkA mediates the multiple effects of NGF, which include neuronal differentiation, neural proliferation, nociceptor response, and avoidance of programmed cell death. [8]

The binding of NGF to TrkA leads to a ligand-induced dimerization, and a proposed mechanism by which this receptor and ligand interact is that two TrkA receptors associate with a single NGF ligand. [9] This interaction leads to a cross linking dimeric complex where parts of the ligand-binding domains on TrkA are associated with their respective ligands. [9] TrkA has five binding domains on its extracellular portion, and the domain TrkA-d5 folds into an immunoglobulin-like domain which is critical and adequate for the binding of NGF. [10] After being immediately bound by NGF, the NGF/TrkA complex is brought from the synapse to the cell body through endocytosis where it then activates the NGF-dependent transcriptional program. [9] Upon activation, the tyrosine residues are phosphorylated within the cytoplasmic domain of TrkA, and these residues then recruit signaling molecules, following several pathways that lead to the differentiation and survival of neurons. [11] Two pathways that this complex acts to promote growth is through the Ras/MAPK pathway and the PI3K/Akt pathway. [9]

Family members

The three transmembrane receptors TrkA, TrkB, and TrkC (encoded by the genes NTRK1, NTRK2, and NTRK3 respectively) make up the Trk receptor family. [12] This family of receptors are all activated by protein nerve growth factors, or neurotrophins. Also, there are other neurotrophic factors structurally related to NGF: BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF, TrkB is bound and activated by BDNF, NT-4, and NT-3. Further, TrkC binds and is activated by NT-3. [13] In one study, the Trk gene was removed from embryonic mice stem cells which led to severe neurological disease, causing most mice to die one month after birth. [14] Thus, Trk is the mediator of developmental and growth processes of NGF, and plays a critical role in the development of the nervous system in many organisms.

There is one other NGF receptor besides TrkA, called the "LNGFR" (for "Low-affinity nerve growth factor receptor "). As opposed to TrkA, the LNGFR plays a somewhat less clear role in NGF biology. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity – since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that in the absence of a co-expressed TrkA, the LNGFR may signal a cell to die via apoptosis – so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.

Role in disease

There are several studies that highlight TrkA's role in various diseases. [15] In one study conducted on two rat models, an inhibition of TrkA with AR786 led to a reduction in joint swelling, joint damage, and pain caused by inflammatory arthritis. [15] Thus, blocking the binding of NGF allows for the alleviation of side effects from inherited arthritis, potentially highlighting a model to aid human inflammatory arthritis. [15]

In one study done on patients with functional dyspepsia, scientists found a significant increase in TrkA and nerve growth factor in gastric mucosa. [16] The increase of TrkA and nerve growth factor is linked to indigestion and gastric symptoms in patients, thus this increase may be linked with the development of functional dyspepsia. [16]

In one study, a total absence of TrkA receptor was found in keratoconus-affected corneas, along with an increased level of repressor isoform of Sp3 transcription factor. [17]

Gene fusions involving NTRK1 have been shown to be oncogenic, leading to the constitutive TrkA activation. [18] In a research study by Vaishnavi A. et al., NTRK1 fusions are estimated to occur in 3.3% of lung cancer as assessed through next generation sequencing or fluorescence in situ hybridization. [18]

While in some contexts, Trk A is oncogenic, in other contexts TrkA has the ability to induced terminal differentiation in cancer cells, halting cellular division. In some cancers, like neuroblastoma, TrkA is seen as a good prognostic marker as it is linked to spontaneous tumor regression. [19]

Regulation

The levels of distinct proteins can be regulated by the "ubiquitin/proteasome" system. In this system, a small (7–8 kd)protein called "ubiquitin" is affixed to a target protein, and is thereby targeted for destruction by a structure called the "proteasome". TrkA is targeted for proteasome-mediated destruction by an "E3 ubiquitin ligase" called NEDD4-2. [20] This mechanism may be a distinct way to control the survival of a neuron. The extent and maybe type of TrkA ubiquitiniation can be regulated by the other, unrelated receptor for NGF, p75NTR.

Interactions

TrkA has been shown to interact with:

Ligands

TRKA receptor domain 5 (purple) bound to NGF (red) Wikipedia trka.png
TRKA receptor domain 5 (purple) bound to NGF (red)

Small molecules such as amitriptyline and gambogic acid derivatives have been claimed to activate TrkA. Amitriptyline activates TrkA and facilitates the heterodimerization of TrkA and TrkB in the absence of NGF. Binding of amitriptyline to TrkA occurs to the Leucine Rich Region (LRR) of the extracellular domain of the receptor, which is distinct from the NGF binding site. Amitryptiline possesses neurotrophic activity both in-vitro and in-vivo (mouse model). [37] Gambogic amide, a derivative of gambogic acid, selectively activates TrkA (but not TrkB and TrkC) both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA. [38]

Role in cancer

TrkA has a dual role in cancer. TrkA was originally cloned from a colon tumor; the cancer occurred via a translocation, which resulted in the activation of the TrkA kinase domain. Although originally identified as an oncogenic fusion in 1982, [39] only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. The mechanism of activation of the Human Trk oncogene is suspected to involve a folding of its kinase domain, leading the receptor to remain constitutively active. [40] In contrast, Trk A also has the potential to induce differentiation and spontaneous regression of cancer in infants. [19]

Inhibitors in development

There are several Trk inhibitors that have been FDA approved, and have been clinically seen to counteract the effects of Trk over-expression by acting as a Trk inhibitor. [41]

Entrectinib (formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in trkA, trkB, and trkC (coded by NTRK1, NTRK2, and NTRK3 genes) that is currently in phase 2 clinical testing. [42]

""Larotrectinib"" is an inhibitor to all of the Trk receptors (TrkA, TrkB, and TrkC) and the drug is used as a treatment for tumors with Trk fusions. [12] A clinical study analyzing the efficiency of the drug found that Larotrectinib was an effective anti tumor treatment, and worked efficiently regardless of age of the patient or tumor type; additionally, the drug did not have long lasting side effects, highlighting the beneficial use of this drug in treating Trk fusions. [12]

Related Research Articles

Brain-derived neurotrophic factor Protein

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

Neurotrophin

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

Nerve growth factor Mammalian protein found in Homo sapiens

Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

ABL (gene) Human protein-coding gene on chromosome 9

Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

Tropomyosin receptor kinase B

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".

Low-affinity nerve growth factor receptor Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

Tropomyosin receptor kinase C

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

Receptor tyrosine kinase Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

Neurotrophin-3

Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.

Neurotrophin-4 Protein-coding gene in the species Homo sapiens

Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase.

ETV6 Protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

FRS2

Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.

SHC3 Protein-coding gene in the species Homo sapiens

SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene.

ROS1

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.

ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm of chromosome 12 at position p13.2 and the NTRK3 gene located on the long arm of chromosome 15 at position q25.3 to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3. ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase domain of the NTRK3 protein. The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network. NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma and subsequently found in secretory breast cancer, Mammary analogue secretory carcinoma of salivary glands, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma, and radiation-induced papillary thyroid carcinoma.

Entrectinib TKI inhibitor used for cancer treatment

Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).

Mammary analogue secretory carcinoma (MASC) is a salivary gland neoplasm that shares a genetic mutation with certain types of breast cancer. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors that was identical to the (12;15)(p13;q25) fusion gene mutation found previously in secretory carcinoma, a subtype of invasive ductal carcinoma of the breast.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198400 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028072 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 8: Atypical neurotransmitters". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. ISBN   9780071481274. Another common feature of neurotrophins is that they produce their physiologic effects by means of the tropomyosin receptor kinase (Trk) receptor family (also known as the tyrosine receptor kinase family). ...
    Trk receptors
    All neurotrophins bind to a class of highly homologous receptor tyrosine kinases known as Trk receptors, of which three types are known: TrkA, TrkB, and TrkC. These transmembrane receptors are glycoproteins whose molecular masses range from 140 to 145 kDa. Each type of Trk receptor tends to bind specific neurotrophins: TrkA is the receptor for NGF, TrkB the receptor for BDNF and NT-4, and TrkC the receptor for NT-3.However, some overlap in the specificity of these receptors has been noted.
  6. Martin-Zanca D, Hughes SH, Barbacid M (April 1986). "A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences". Nature. 319 (6056): 743–8. Bibcode:1986Natur.319..743M. doi:10.1038/319743a0. PMID   2869410. S2CID   4316805.
  7. "Entrez Gene: NTRK1 neurotrophic tyrosine kinase, receptor, type 1".
  8. Martin-Zanca D, Hughes SH, Barbacid M (2016). "A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences". Nature. 319 (6056): 743–8. doi: 10.1136/annrheumdis-2014-207203 . PMID   2869410.
  9. 1 2 3 4 Stoleru B, Popescu A, Tache D, Neamtu O, Emami G, Tataranu L, Buteica A, Dricu A, Purcaru S (2013). "Tropomyosin-Receptor-Kinases Signaling in the Nervous System". Maedica. 8 (1): 43–48. PMC   3749761 . PMID   24023598.
  10. 1 2 Wiesmann C, Ultsch MH, Bass SH, de Vos AM (September 1999). "Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor". Nature. 401 (6749): 184–8. Bibcode:1999Natur.401..184W. doi:10.1038/43705. PMID   10490030. S2CID   4337786.
  11. Marlin MC, Li G (2015). "Biogenesis and function of the NGF/TrkA signaling endosome". International Review of Cell and Molecular Biology. 314: 239–57. doi:10.1016/bs.ircmb.2014.10.002. ISBN   9780128022832. PMC   4307610 . PMID   25619719.
  12. 1 2 3 McPhail CW (December 1965). "Current advances in public health dentistry". Canadian Journal of Public Health. 56 (12): 512–6. doi:10.1056/NEJMoa1714448. PMC   5857389 . PMID   29466156.
  13. Benito-Gutiérrez E, Garcia-Fernàndez J, Comella JX (February 2006). "Origin and evolution of the Trk family of neurotrophic receptors". Molecular and Cellular Neurosciences. 31 (2): 179–92. doi:10.1016/j.mcn.2005.09.007. PMID   16253518. S2CID   25232377.
  14. Smeyne RJ, Klein R, Schnapp A, Long LK, Bryant S, Lewin A, et al. (March 1994). "Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene". Nature. 368 (6468): 246–9. Bibcode:1994Natur.368..246S. doi:10.1038/368246a0. PMID   8145823. S2CID   4318721.
  15. 1 2 3 Ashraf S, Bouhana KS, Pheneger J, Andrews SW, Walsh DA (May 2016). "Selective inhibition of tropomyosin-receptor-kinase A (TrkA) reduces pain and joint damage in two rat models of inflammatory arthritis". Arthritis Research & Therapy. 18 (1): 97. doi: 10.1186/s13075-016-0996-z . PMC   4857260 . PMID   27145816.
  16. 1 2 Shi H, Zhu S, Qin B, Wang L, Yang J, Lu G, Dai F (December 2019). "Nerve growth factor and Tropomyosin receptor kinase A are increased in the gastric mucosa of patients with functional dyspepsia". BMC Gastroenterology. 19 (1): 221. doi:10.1186/s12876-019-1133-7. PMC   6924065 . PMID   31856738.
  17. Lambiase A, Merlo D, Mollinari C, Bonini P, Rinaldi AM, D' Amato M, et al. (November 2005). "Molecular basis for keratoconus: lack of TrkA expression and its transcriptional repression by Sp3". Proceedings of the National Academy of Sciences of the United States of America. 102 (46): 16795–800. Bibcode:2005PNAS..10216795L. doi: 10.1073/pnas.0508516102 . PMC   1283852 . PMID   16275928.
  18. 1 2 Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al. (November 2013). "Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer". Nature Medicine. 19 (11): 1469–1472. doi:10.1038/nm.3352. PMC   3823836 . PMID   24162815.
  19. 1 2 Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer R, Varela CR, Light JE, Kolla V, Evans AE (May 2009). "Trk receptor expression and inhibition in neuroblastomas". Clinical Cancer Research. 15 (10): 3244–50. doi:10.1158/1078-0432.CCR-08-1815. PMC   4238907 . PMID   19417027.
  20. Yu T, Calvo L, Anta B, López-Benito S, Southon E, Chao MV, et al. (April 2011). "Regulation of trafficking of activated TrkA is critical for NGF-mediated functions". Traffic. 12 (4): 521–34. doi:10.1111/j.1600-0854.2010.01156.x. PMC   3547592 . PMID   21199218.
  21. 1 2 3 4 Koch A, Mancini A, Stefan M, Niedenthal R, Niemann H, Tamura T (March 2000). "Direct interaction of nerve growth factor receptor, TrkA, with non-receptor tyrosine kinase, c-Abl, through the activation loop". FEBS Letters. 469 (1): 72–6. doi: 10.1016/S0014-5793(00)01242-4 . PMID   10708759.
  22. Yano H, Cong F, Birge RB, Goff SP, Chao MV (February 2000). "Association of the Abl tyrosine kinase with the Trk nerve growth factor receptor". Journal of Neuroscience Research. 59 (3): 356–64. doi:10.1002/(SICI)1097-4547(20000201)59:3<356::AID-JNR9>3.0.CO;2-G. PMID   10679771.
  23. 1 2 3 Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM (April 1999). "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". The Journal of Biological Chemistry. 274 (14): 9861–70. doi: 10.1074/jbc.274.14.9861 . PMID   10092678.
  24. Song C, Perides G, Liu YF (February 2002). "Expression of full-length polyglutamine-expanded Huntingtin disrupts growth factor receptor signaling in rat pheochromocytoma (PC12) cells". The Journal of Biological Chemistry. 277 (8): 6703–7. doi: 10.1074/jbc.M110338200 . PMID   11733534.
  25. MacDonald JI, Gryz EA, Kubu CJ, Verdi JM, Meakin SO (June 2000). "Direct binding of the signaling adapter protein Grb2 to the activation loop tyrosines on the nerve growth factor receptor tyrosine kinase, TrkA". The Journal of Biological Chemistry. 275 (24): 18225–33. doi: 10.1074/jbc.M001862200 . PMID   10748052.
  26. Yamashita H, Avraham S, Jiang S, Dikic I, Avraham H (May 1999). "The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells". The Journal of Biological Chemistry. 274 (21): 15059–65. doi: 10.1074/jbc.274.21.15059 . PMID   10329710.
  27. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, et al. (February 2004). "Sortilin is essential for proNGF-induced neuronal cell death". Nature. 427 (6977): 843–8. Bibcode:2004Natur.427..843N. doi:10.1038/nature02319. PMID   14985763. S2CID   4343450.
  28. Lee R, Kermani P, Teng KK, Hempstead BL (November 2001). "Regulation of cell survival by secreted proneurotrophins". Science. 294 (5548): 1945–8. Bibcode:2001Sci...294.1945L. doi:10.1126/science.1065057. PMID   11729324. S2CID   872149.
  29. Ohmichi M, Decker SJ, Pang L, Saltiel AR (August 1991). "Nerve growth factor binds to the 140 kd trk proto-oncogene product and stimulates its association with the src homology domain of phospholipase C gamma 1" (PDF). Biochemical and Biophysical Research Communications. 179 (1): 217–23. doi:10.1016/0006-291X(91)91357-I. hdl: 2027.42/29169 . PMID   1715690.
  30. 1 2 3 4 Qian X, Riccio A, Zhang Y, Ginty DD (November 1998). "Identification and characterization of novel substrates of Trk receptors in developing neurons". Neuron. 21 (5): 1017–29. doi: 10.1016/S0896-6273(00)80620-0 . PMID   9856458. S2CID   12354383.
  31. 1 2 Nakamura T, Komiya M, Sone K, Hirose E, Gotoh N, Morii H, et al. (December 2002). "Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules". Molecular and Cellular Biology. 22 (24): 8721–34. doi:10.1128/MCB.22.24.8721-8734.2002. PMC   139861 . PMID   12446789.
  32. Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J (March 2001). "The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor". The Journal of Biological Chemistry. 276 (11): 7709–12. doi: 10.1074/jbc.C000869200 . PMID   11244088.
  33. Geetha T, Wooten MW (February 2003). "Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling". The Journal of Biological Chemistry. 278 (7): 4730–9. doi: 10.1074/jbc.M208468200 . PMID   12471037.
  34. Jadhav T, Geetha T, Jiang J, Wooten MW (July 2008). "Identification of a consensus site for TRAF6/p62 polyubiquitination". Biochemical and Biophysical Research Communications. 371 (3): 521–4. doi:10.1016/j.bbrc.2008.04.138. PMC   2474794 . PMID   18457658.
  35. Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, et al. (March 2008). "Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins". The Journal of Biological Chemistry. 283 (11): 6783–9. doi: 10.1074/jbc.M709496200 . PMID   18174161.
  36. Borrello MG, Pelicci G, Arighi E, De Filippis L, Greco A, Bongarzone I, et al. (June 1994). "The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins". Oncogene. 9 (6): 1661–8. PMID   8183561.
  37. Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K (June 2009). "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chemistry & Biology. 16 (6): 644–56. doi:10.1016/j.chembiol.2009.05.010. PMC   2844702 . PMID   19549602.
  38. Jang SW, Okada M, Sayeed I, Xiao G, Stein D, Jin P, Ye K (October 2007). "Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death". Proceedings of the National Academy of Sciences of the United States of America. 104 (41): 16329–34. Bibcode:2007PNAS..10416329J. doi: 10.1073/pnas.0706662104 . PMC   2042206 . PMID   17911251.
  39. Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M (December 1982). "Oncogenes in solid human tumours". Nature. 300 (5892): 539–42. Bibcode:1982Natur.300..539P. doi:10.1038/300539a0. PMID   7144906. S2CID   30179526.
  40. Coulier F, Martin-Zanca D, Ernst M, Barbacid M (January 1989). "Mechanism of activation of the human trk oncogene". Molecular and Cellular Biology. 9 (1): 15–23. doi: 10.1128/mcb.9.1.15 . PMC   362140 . PMID   2538716.
  41. Bailey JJ, Jaworski C, Tung D, Wängler C, Wängler B, Schirrmacher R (May 2020). "Tropomyosin receptor kinase inhibitors: an updated patent review for 2016-2019". Expert Opinion on Therapeutic Patents. 30 (5): 325–339. doi:10.1080/13543776.2020.1737011. PMID   32129124. S2CID   212406547.
  42. "Promising entrectinib clinical trial data". ScienceDaily. 18 April 2016.

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