NTRK1_HUMAN » High affinity nerve growth factor receptor

NTRK1_HUMAN » High affinity nerve growth factor receptor
Magnify NTRK1_HUMAN » High affinity nerve growth factor receptorEnlarged view of image
3D view in GLMol or JMol

gray dot

Download Coordinates

gray dot

Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
NTRK1_HUMAN » High affinity nerve growth factor receptor » Neurotrophic tyrosine kinase receptor type 1;TRK1-transforming tyrosine kinase protein;p140-TrkA;Trk-A;
Hydrophobic Thickness 34.4 ± 3.4 Å
Tilt Angle 6 ± 3°
ΔGtransfer -46.1 kcal/mol
ΔGfold -18.5 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 416-440 (413-445)
Pathways

Apoptosis (KEGG)

Endocytosis (KEGG)

MAPK signaling pathway (KEGG)

Neurotrophin signaling pathway (KEGG)

Pathways in cancer (KEGG)

Signal Transduction (Reactome)

Thyroid cancer (KEGG)

Transcriptional misregulation in cancer (KEGG)

PDB 4crp (282-383), 4gt5 (498-796), 4f0i (498-796), 4pms (501-787), 4pmp (501-787), 4pmm (501-787), 4pmt (501-787), 4aoj (A/B/C=473-796), 2ifg (A/B=36-382), 1he7 (A=285-413), 1shc (B=489-500), 1wwa (X/Y=278-386), 1www (X/Y=282-382)
OPM none
Complexes

NTRK1:NTRK1_HUMAN

Interactions

NTRK1, Complex: Hexamer of high affinity nerve growth factor receptor, PDBID: 4AOJ

PTPRB, Complex: NTRK1:PTPRB

PTPRC, Complex: PTPRC:NTRK1

PTPRG, Complex: NTRK1:PTPRG

PTPRJ, Complex: NTRK1:PTPRJ

PTPRO, Complex: NTRK1:PTPRO

SORT, Complex: NTRK1:SORT, PubMed

TNR16, Complex: TNR16:NTRK1, PubMed

Domains

AA: 151-192, PDBID: 2IFG, Subunit A, Seq Identity:100%, Tyrosine-protein kinase receptor C2 Ig-like domain

AA: 510-781, PDBID: 4AOJ, Subunit C, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for NTRK1_HUMAN » 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, it 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. 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.

FUNCTION: Isoform TrkA-III is resistant to NGF, constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras- MAPK signaling cascade. Antagonizes the anti-proliferative NGF- NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: The pro-survival signaling effect of NTRK1 in neurons requires its endocytosis into signaling early endosomes and its retrograde axonal transport. This is regulated by different proteins including CFL1, RAC1 and SORT1. NTF3 is unable to induce this signaling probably due to the lability of the NTF3- NTRK1 complex in endosomes. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades (By similarity). Regulated by NGFR (By similarity).

SUBUNIT: Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer. Interacts with SQSTM1; bridges NTRK1 to NGFR. Forms a ternary complex with NGFR and KIDINS220; this complex is affected by the expression levels of KIDINS220 and an increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1 (By similarity). Interacts with SH2D1A; regulates NTRK1 (By similarity). Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation. Interacts (phosphorylated) with SH2B1 and SH2B2. Interacts with GRB2. Interacts with PIK3R1. Interacts with FRS2. Interacts with SORT1; may regulate NTRK1 anterograde axonal transport. Interacts with RAB7A (By similarity). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a nerve growth factor (NGF)-dependent manner (By similarity). Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation (By similarity).

TISSUE SPECIFICITY: Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors.

INDUCTION: Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it.

DOMAIN: The transmembrane domain mediates interaction with KIDINS220.

DOMAIN: The extracellular domain mediates interaction with NGFR.

DISEASE: Congenital insensitivity to pain with anhidrosis (CIPA) OMIM: Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. mutations affecting the gene represented in this entry.

DISEASE: Thyroid papillary carcinoma (TPC) OMIM: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3"-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3"-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5"-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein.

MISCELLANEOUS: Trk also stands for tropomyosin-related kinase since it was first isolated as an oncogenic protein which was the result of a fusion between the tropomyosin gene TPM3 and NTRK1.

UniProt features for NTRK1_HUMAN » High affinity nerve growth factor receptor
SIGNAL 1 32 Potential.
CHAIN 33 796 High affinity nerve growth factor receptor.
REPEAT 90 113 LRR 1.
REPEAT 116 137 LRR 2.
DOMAIN 148 193 LRRCT.
DOMAIN 194 283 Ig-like C2-type 1.
DOMAIN 299 365 Ig-like C2-type 2.
DOMAIN 510 781 Protein kinase.
REGION 469 490 Interaction with SQSTM1 (By similarity).
ACT_SITE 650 650 Proton acceptor (By similarity).
SITE 398 399 Breakpoint for translocation to form TRK and TRK-T3.
SITE 486 486 Breakpoint for translocation to form TRK- T1.
SITE 496 496 Interaction with SHC1.
SITE 791 791 Interaction with PLCG1.
DISULFID 154 191
DISULFID 215 265
Amino Acid Sequence for NTRK1_HUMAN » High affinity nerve growth factor receptor
MLRGGRRGQL GWHSWAAGPG SLLAWLILAS AGAAPCPDAC CPHGSSGLRC TRDGALDSLH HLPGAENLTE LYIENQQHLQ HLELRDLRGL GELRNLTIVK SGLRFVAPDA FHFTPRLSRL NLSFNALESL SWKTVQGLSL QELVLSGNPL HCSCALRWLQ RWEEEGLGGV PEQKLQCHGQ GPLAHMPNAS CGVPTLKVQV PNASVDVGDD VLLRCQVEGR GLEQAGWILT ELEQSATVMK SGGLPSLGLT LANVTSDLNR KNVTCWAEND VGRAEVSVQV NVSFPASVQL HTAVEMHHWC IPFSVDGQPA PSLRWLFNGS VLNETSFIFT EFLEPAANET VRHGCLRLNQ PTHVNNGNYT LLAANPFGQA SASIMAAFMD NPFEFNPEDP IPVSFSPVDT NSTSGDPVEK KDETPFGVSV AVGLAVFACL FLSTLLLVLN KCGRRNKFGI NRPAVLAPED GLAMSLHFMT LGGSSLSPTE GKGSGLQGHI IENPQYFSDA CVHHIKRRDI VLKWELGEGA FGKVFLAECH NLLPEQDKML VAVKALKEAS ESARQDFQRE AELLTMLQHQ HIVRFFGVCT EGRPLLMVFE YMRHGDLNRF LRSHGPDAKL LAGGEDVAPG PLGLGQLLAV ASQVAAGMVY LAGLHFVHRD LATRNCLVGQ GLVVKIGDFG MSRDIYSTDY YRVGGRTMLP IRWMPPESIL YRKFTTESDV WSFGVVLWEI FTYGKQPWYQ LSNTEAIDCI TQGRELERPR ACPPEVYAIM RGCWQREPQQ RHSIKDVHAR LQALAQAPPV YLDVLG