High affinity nerve growth factor receptor

Function

Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand. Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.

Classification

Family (Pfam)

PF13855 LRR_8, PF16920 LRRCT_2, PF07714 PK_Tyr_Ser-Thr, PF18613 TrkA_TMD

InterPro

Cys-rich_flank_reg_C, Ig-like_dom, Ig-like_dom_sf, Ig-like_fold, Kinase-like_dom_sf, Leu-rich_rpt, LRR_dom_sf, NTRK, NTRK1, NTRK_LRRCT, Prot_kinase_dom, Protein_kinase_ATP_BS, RTK, Ser-Thr/Tyr_kinase_cat_dom, TrkA_TMD, Tyr_kinase_AS, Tyr_kinase_cat_dom, Tyr_kinase_rcpt_2_CS

Functional cluster

Secreted Growth Factors & Cytokines

Experimental structures · PDB · 65

• 1HE7 X-ray 2.00A
• 1SHC NMR
• 1WWA X-ray 2.50A
• 1WWW X-ray 2.20A
• 2IFG X-ray 3.40A
• 2N90 NMR
• 4AOJ X-ray 2.75A
• 4CRP NMR
• 4F0I X-ray 2.30A
• 4GT5 X-ray 2.40A
• 4PMM X-ray 2.00A
• 4PMP X-ray 1.80A
• … and 53 more

A predicted model is available from AlphaFold.

Gene Ontology · 64

• GO:0030424 axon
• GO:0009986 cell surface
• GO:0030425 dendrite
• GO:0005769 early endosome
• GO:0031901 early endosome membrane
• GO:0010008 endosome membrane
• GO:0005770 late endosome
• GO:0031902 late endosome membrane
• GO:0005739 mitochondrion
• GO:0043025 neuronal cell body
• GO:0005886 plasma membrane
• GO:0032991 protein-containing complex
• GO:0043235 receptor complex
• GO:0055038 recycling endosome membrane
• GO:0005524 ATP binding
• GO:0005004 GPI-linked ephrin receptor activity
• GO:0042802 identical protein binding
• GO:0019900 kinase binding
• GO:0048406 nerve growth factor binding
• GO:0010465 nerve growth factor receptor activity
• GO:0043121 neurotrophin binding
• GO:0005166 neurotrophin p75 receptor binding
• GO:0005030 neurotrophin receptor activity
• GO:0042803 protein homodimerization activity
• GO:0004713 protein tyrosine kinase activity
• GO:0004714 transmembrane receptor protein tyrosine kinase activity
• GO:0007411 axon guidance
• GO:0060385 axonogenesis involved in innervation
• GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway
• GO:1990090 cellular response to nerve growth factor stimulus
• GO:0071316 cellular response to nicotine
• GO:0007623 circadian rhythm
• GO:0050966 detection of mechanical stimulus involved in sensory perception of pain
• GO:0050965 detection of temperature stimulus involved in sensory perception of pain
• GO:0007611 learning or memory
• GO:0043066 negative regulation of apoptotic process
• GO:0008285 negative regulation of cell population proliferation
• GO:0043524 negative regulation of neuron apoptotic process
• GO:0038180 nerve growth factor signaling pathway
• GO:0048666 neuron development
• GO:0031175 neuron projection development
• GO:0048011 neurotrophin TRK receptor signaling pathway
• GO:0021553 olfactory nerve development
• GO:0038083 peptidyl-tyrosine autophosphorylation
• GO:0018108 peptidyl-tyrosine phosphorylation
• GO:0045766 positive regulation of angiogenesis
• GO:0070374 positive regulation of ERK1 and ERK2 cascade
• GO:0043547 positive regulation of GTPase activity
• GO:0010976 positive regulation of neuron projection development
• GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
• GO:0043068 positive regulation of programmed cell death
• GO:0046579 positive regulation of Ras protein signal transduction
• GO:0051968 positive regulation of synaptic transmission, glutamatergic
• GO:0010623 programmed cell death involved in cell development
• GO:0046777 protein autophosphorylation
• GO:0006468 protein phosphorylation
• GO:0048678 response to axon injury
• GO:0051602 response to electrical stimulus
• GO:0051599 response to hydrostatic pressure
• GO:0031667 response to nutrient levels
• GO:0009410 response to xenobiotic stimulus
• GO:0060009 Sertoli cell development
• GO:0007283 spermatogenesis
• GO:0048485 sympathetic nervous system development

Disease associations

• hereditary sensory and autonomic neuropathy type 4 MONDO:0009746

Drugs targeting this protein · 14

• REGORAFENIB inhibitor
• ENTRECTINIB inhibitor
• ALTIRATINIB inhibitor
• AZD-7451 inhibitor
• GZ-389988 inhibitor
• LAROTRECTINIB inhibitor
• LAROTRECTINIB SULFATE inhibitor
• PEGCANTRATINIB inhibitor
• SELITRECTINIB inhibitor
• REPOTRECTINIB inhibitor
• TALETRECTINIB inhibitor
• MILCICLIB inhibitor
• LESTAURTINIB inhibitor
• CEP-2563 DIHYDROCHLORIDE inhibitor

Related proteins · sequence + function similarity

• High affinity nerve growth factor receptor 0.98
• High affinity nerve growth factor receptor 0.98
• High affinity nerve growth factor receptor 0.91
• Tyrosine-protein kinase receptor UFO 0.80
• Fibroblast growth factor receptor 4 0.80
• Tyrosine-protein kinase receptor UFO 0.78
• Tyrosine-protein kinase receptor TYRO3 0.78
• Tyrosine-protein kinase receptor TYRO3 0.76
• Tyrosine-protein kinase receptor TYRO3 0.75
• Amphoterin-induced protein 3 0.75
• Fibroblast growth factor receptor 4 0.74
• Fibroblast growth factor receptor 4 0.74

Co-cited proteins · studied together in the literature

• Beta-nerve growth factor 4 shared papers
• High affinity nerve growth factor receptor 5 shared papers
• Large ribosomal subunit protein eL8 1 shared papers
• NT-3 growth factor receptor 2 shared papers
• Protein TFG 1 shared papers
• Tropomyosin alpha-3 chain 1 shared papers
• BDNF/NT-3 growth factors receptor 2 shared papers
• Venom nerve growth factor 1 shared papers
• SHC-transforming protein 1 3 shared papers
• Sortilin 1 shared papers
• ADP-ribosylation factor-binding protein GGA3 1 shared papers
• Nucleoprotein TPR 1 shared papers

Literature · 44 cited papers

• Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype. Am. J. Med. Genet. A · 2017
• Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies. J. Peripher. Nerv. Syst. · 2017
• A comprehensive functional analysis of NTRK1 missense mutations causing hereditary sensory and autonomic neuropathy type IV (HSAN IV). Hum. Mutat. · 2017
• Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3). J. Biol. Chem. · 2016
• GGA3 mediates TrkA endocytic recycling to promote sustained Akt phosphorylation and cell survival. Mol. Biol. Cell · 2015
• Structural and functional insights into lipid-bound nerve growth factors. FASEB J. · 2012
• Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J. Neurol. · 2012
• Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat. Neurosci. · 2011
• Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. Neuromuscul. Disord. · 2008
• Patterns of somatic mutation in human cancer genomes. Nature · 2007
• Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. Neuron · 2007
• The DNA sequence and biological annotation of human chromosome 1. Nature · 2006
• … and 32 more in the literature graph