NTRK2_HUMAN » BDNF/NT-3 growth factors receptor

NTRK2_HUMAN » BDNF/NT-3 growth factors receptor
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NTRK2_HUMAN » BDNF/NT-3 growth factors receptor » GP145-TrkB;Trk-B; Neurotrophic tyrosine kinase receptor type 2;TrkB tyrosine kinase;Tropomyosin-related kinase B;
Hydrophobic Thickness 34.0 ± 1.2 Å
Tilt Angle 0 ± 0°
ΔGtransfer -45.4 kcal/mol
ΔGfold -24.5 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 429-457 (424-460)
Pathways

Alcoholism (KEGG)

MAPK signaling pathway (KEGG)

Neurotrophin signaling pathway (KEGG)

Signal Transduction (Reactome)

PDB 1wwb (283-385), 4asz (527-822), 4at3 (527-822), 4at4 (527-822), 4at5 (527-822), 2mfq (B=497-519), 1hcf (X/Y=286-383)
OPM none
Complexes none
Interactions

EGFR, Complex: EGFR:NTRK2, PubMed

LIGO1, Complex: LIGO1:NTRK2, PubMed

SORT, Complex: NTRK2:SORT, PubMed

TNR16, Complex: NTRK2:TNR16, PubMed

Domains

AA: 31-60, PDBID: 2V70, Subunit C, Seq Identity:32%, Leucine rich repeat N-terminal domain

AA: 91-150, PDBID: 4PBV, Subunit A, Seq Identity:48%, Leucine rich repeat

AA: 151-195, PDBID: 4PBV, Subunit A, Seq Identity:40%, Tyrosine-protein kinase receptor C2 Ig-like domain

AA: 197-283, PDBID: 4X83, Subunit A, Seq Identity:33%, Immunoglobulin I-set domain

AA: 298-377, PDBID: 1HCF, Subunit Y, Seq Identity:100%, Immunoglobulin I-set domain

AA: 538-807, PDBID: 4ASZ, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for NTRK2_HUMAN » BDNF/NT-3 growth factors receptor
FUNCTION: Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin- 4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon 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. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin- dependent calcium signaling in glial cells and mediate communication between neurons and glia.

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

ENZYME REGULATION: The neuronal activity and the influx of calcium positively regulate the kinase activity and the internalization of the receptor which are both important for active signaling. Regulated by NGFR that may control the internalization of the receptor. NGFR may also stimulate the activation by BDNF compared to NTF3 and NTF4. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. The formation of active receptors dimers able to fully transduce the ligand-mediated signal, may be negatively regulated by the formation of inactive heterodimers with the non-catalytic isoforms (By similarity).

SUBUNIT: Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Interacts (phosphorylated upon activation by BDNF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by BDNF) with PLCG1 and/or PLCG2; mediates PLCG1 phosphorylation and activation. Interacts with SH2B1 and SH2B2. Interacts with NGFR; may regulate the ligand specificity of the receptor. Interacts (phosphorylated upon ligand-binding) with SH2D1A; regulates NTRK2. Interacts with SQSTM1 and KIDINS220 (By similarity). Interacts (phosphorylated upon ligand-binding) with FRS2; activates the MAPK signaling pathway.

TISSUE SPECIFICITY: Isoform TrkB is expressed in the central and peripheral nervous system. In the central nervous system (CNS), expression is observed in the cerebral cortex, hippocampus, thalamus, choroid plexus, granular layer of the cerebellum, brain stem, and spinal cord. In the peripheral nervous system, it is expressed in many cranial ganglia, the ophthalmic nerve, the vestibular system, multiple facial structures, the submaxillary glands, and dorsal root ganglia. Isoform TrkB-T1 is mainly expressed in the brain but also detected in other tissues including pancreas, kidney and heart. Isoform TrkB-T-Shc is predominantly expressed in the brain.

DEVELOPMENTAL STAGE: Widely expressed in fetal brain.

DISEASE: Obesity, hyperphagia, and developmental delay (OBHD) OMIM: A disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language. disease is caused by mutations affecting the gene represented in this entry.

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

UniProt features for NTRK2_HUMAN » BDNF/NT-3 growth factors receptor
SIGNAL 1 31
CHAIN 32 822 BDNF/NT-3 growth factors receptor.
DOMAIN 32 61 LRRNT.
REPEAT 92 113 LRR 1.
REPEAT 116 137 LRR 2.
DOMAIN 148 196 LRRCT.
DOMAIN 197 282 Ig-like C2-type 1.
DOMAIN 295 365 Ig-like C2-type 2.
DOMAIN 538 807 Protein kinase.
ACT_SITE 676 676 Proton acceptor (By similarity).
SITE 516 516 Interaction with SHC1 (By similarity).
SITE 706 706 Interaction with SH2D1A (By similarity).
SITE 817 817 Interaction with PLCG1 (By similarity).
DISULFID 32 38
DISULFID 36 45
DISULFID 152 176
DISULFID 154 194
DISULFID 218 266
DISULFID 302 345
Amino Acid Sequence for NTRK2_HUMAN » BDNF/NT-3 growth factors receptor
MSSWIRWHGP AMARLWGFCW LVVGFWRAAF ACPTSCKCSA SRIWCSDPSP GIVAFPRLEP NSVDPENITE IFIANQKRLE IINEDDVEAY VGLRNLTIVD SGLKFVAHKA FLKNSNLQHI NFTRNKLTSL SRKHFRHLDL SELILVGNPF TCSCDIMWIK TLQEAKSSPD TQDLYCLNES SKNIPLANLQ IPNCGLPSAN LAAPNLTVEE GKSITLSCSV AGDPVPNMYW DVGNLVSKHM NETSHTQGSL RITNISSDDS GKQISCVAEN LVGEDQDSVN LTVHFAPTIT FLESPTSDHH WCIPFTVKGN PKPALQWFYN GAILNESKYI CTKIHVTNHT EYHGCLQLDN PTHMNNGDYT LIAKNEYGKD EKQISAHFMG WPGIDDGANP NYPDVIYEDY GTAANDIGDT TNRSNEIPST DVTDKTGREH LSVYAVVVIA SVVGFCLLVM LFLLKLARHS KFGMKGPASV ISNDDDSASP LHHISNGSNT PSSSEGGPDA VIIGMTKIPV IENPQYFGIT NSQLKPDTFV QHIKRHNIVL KRELGEGAFG KVFLAECYNL CPEQDKILVA VKTLKDASDN ARKDFHREAE LLTNLQHEHI VKFYGVCVEG DPLIMVFEYM KHGDLNKFLR AHGPDAVLMA EGNPPTELTQ SQMLHIAQQI AAGMVYLASQ HFVHRDLATR NCLVGENLLV KIGDFGMSRD VYSTDYYRVG GHTMLPIRWM PPESIMYRKF TTESDVWSLG VVLWEIFTYG KQPWYQLSNN EVIECITQGR VLQRPRTCPQ EVYELMLGCW QREPHMRKNI KGIHTLLQNL AKASPVYLDI LG