Tyrosine kinase receptor

Function

Tyrosine kinase receptor or high affinity nerve growth factor receptor (TRK-A) play an important role in cellular processes like growth, motility, differentiation and metabolism^[1]. Nerve growth factor (NGF) is a neutrotrophin which binds with high affinity to TRK. The binding of NGF to TRK-A activates the latter which undergoes dimerization and autophosphorylation at several Tyr residues that selectively trigger activity in several intercellular signaling pathways via binding of specific effector proteins^[2]. There are 3 members to the TRK family: TRK-A, TRK-B and TRK-C. All of them bind preferentially - NGF, neurotrophin-4, Brain-Derived Neurotrophic Factor (BDNF), and neurotrophin-3.

• Trk-C is involved in the biology favourable neuroblastomas^[3].
• Alk tyrosine kinase receptor is expressed in neurons of the central nervous system signaling growth and differentiation of neurons^[4].
• RET tyrosine kinase receptor (Rearranged during transfection) plays a role in the development of the central and peripheral nervous systems^[5].
• MuSK tyrosine kinase receptor (muscle-specific kinase) plays a role in signaling at the formation of neuromuscular junctions^[6].

See also:

• High affinity nerve growth factor receptor
• Neurotrophin.
• Receptor tyrosine kinases

Disease

Disregulation of TRK-A signalling leads to cancer.

Relevance

TRK-A inhibitors are suitable alternatives to teatment of neoendocrine tumors like pheochromocytomas and ^[7].

Structural highlights

TRK-A contains an extracellular ligand binding domain (LBD), a transmembrane helix and an intracellular region which contains the kinase domain. The kinase domain (PDB code 4yne) contains the tripeptide DFG which flips out in TRK-A inactivated form. (PDB code 4yne). Water molecules are shown as red spheres. The structure of the complex of TRK-A with the phenylpyrrolidine derivative shows the inhibitor forming hydrogen bonds to Met620 and Lys572 residues and π-π interactions of it with Phe617 and Phe 698 ^[8].

The (PDB code 2ifg) is a 2:2 dimer. The C-terminal immunoglobulin-like domain interacts with the NGF^[9]. The extracellular domain of TRK-A contains flanked by (in yellow), 2 immunoglobulin-like domains and the nerve growth factor (NGF) binding domain.

3D Structures tyrosine kinase receptor

Tyrosine kinase receptor 3D structures

References

1. ↑ Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018 Feb 19;17(1):58. doi: 10.1186/s12943-018-0782-4. PMID:29455648 doi:http://dx.doi.org/10.1186/s12943-018-0782-4
2. ↑ Deinhardt K, Chao MV. Trk receptors. Handb Exp Pharmacol. 2014;220:103-19. doi: 10.1007/978-3-642-45106-5_5. PMID:24668471 doi:http://dx.doi.org/10.1007/978-3-642-45106-5_5
3. ↑ Yamashiro DJ, Liu XG, Lee CP, Nakagawara A, Ikegaki N, McGregor LM, Baylin SB, Brodeur GM. Expression and function of Trk-C in favourable human neuroblastomas. Eur J Cancer. 1997 Oct;33(12):2054-7. PMID:9516852 doi:10.1016/s0959-8049(97)00309-2
4. ↑ Motegi A, Fujimoto J, Kotani M, Sakuraba H, Yamamoto T. ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth. J Cell Sci. 2004 Jul 1;117(Pt 15):3319-29. PMID:15226403 doi:10.1242/jcs.01183
5. ↑ Mahato AK, Sidorova YA. RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer. Int J Mol Sci. 2020 Sep 26;21(19):7108. PMID:32993133 doi:10.3390/ijms21197108
6. ↑ Hubbard SR, Gnanasambandan K. Structure and activation of MuSK, a receptor tyrosine kinase central to neuromuscular junction formation. Biochim Biophys Acta. 2013 Oct;1834(10):2166-9. PMID:23467009 doi:10.1016/j.bbapap.2013.02.034
7. ↑ Cassol CA, Winer D, Liu W, Guo M, Ezzat S, Asa SL. Tyrosine kinase receptors as molecular targets in pheochromocytomas and paragangliomas. Mod Pathol. 2014 Aug;27(8):1050-62. doi: 10.1038/modpathol.2013.233. Epub 2014, Jan 3. PMID:24390213 doi:http://dx.doi.org/10.1038/modpathol.2013.233
8. ↑ Choi HS, Rucker PV, Wang Z, Fan Y, Albaugh P, Chopiuk G, Gessier F, Sun F, Adrian F, Liu G, Hood T, Li N, Jia Y, Che J, McCormack S, Li A, Li J, Steffy A, Culazzo A, Tompkins C, Phung V, Kreusch A, Lu M, Hu B, Chaudhary A, Prashad M, Tuntland T, Liu B, Harris J, Seidel HM, Loren J, Molteni V. (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors. ACS Med Chem Lett. 2015 Mar 16;6(5):562-7. doi: 10.1021/acsmedchemlett.5b00050., eCollection 2015 May 14. PMID:26005534 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00050
9. ↑ Wehrman T, He X, Raab B, Dukipatti A, Blau H, Garcia KC. Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors. Neuron. 2007 Jan 4;53(1):25-38. PMID:17196528 doi:10.1016/j.neuron.2006.09.034