14.15: Enzyme-linked Receptors
Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5, while TrkC is specific for neurotrophin-3.
The Trk receptors have a single transmembrane domain, with a growth factor binding site on the extracellular portion and an enzyme activation site intracellularly. Trk receptors can be monomeric or dimerized, where two Trk receptors are linked. Either a single growth factor binds two monomeric receptors causing them to dimerize, or the growth factor binds both sites on a pre-dimerized receptor to activate the receptor.
Once the receptors are bound, the activated tyrosine kinases cross-phosphorylate the tyrosines using phosphate from ATP and donating them to each other. Phosphorylated tyrosines are recognized as docking sites by intracellular signaling protein domains, such as the Src homology 2 (SH2). Each docking site is used by different signaling proteins, which increases the variety of downstream effects regulated by these receptors.
The interaction between NGF and TrkA has garnered attention for its role in the progression of Alzheimer's disease, a disorder in which neurons develop amyloid plaques. Amyloid-beta is a cytotoxic fragment of the amyloid precursor protein (APP). It is hypothesized that binding NGF to the TrkA receptor decreases the generation of amyloid-beta by joining APP to the TrkA receptor. This eliminates the ability of beta-secretase 1 (BACE1) to cleave APP into amyloid-beta. Furthermore, the TrkA receptor can shuttle APP to the Golgi, where BACE1 enzymes are rare. In the brain of Alzheimer's patients, there is a decreased generation of TrkA/APP complex in areas critical to learning and memory, like the hippocampus.