Gamma-secretase-dependent signaling of receptor tyrosine kinases

Abstract

Human genome harbors 55 receptor tyrosine kinases (RTK). At least half of the RTKs have been reported to be cleaved by gamma-secretase-mediated regulated intramembrane proteolysis. The two-step process involves releasing the RTK ectodomain to the extracellular space by proteolytic cleavage called shedding, followed by cleavage in the RTK transmembrane domain by the gamma-secretase complex resulting in release of a soluble RTK intracellular domain. This intracellular domain, including the tyrosine kinase domain, can in turn translocate to various cellular compartments, such as the nucleus or proteasome. The soluble intracellular domain may interact with transcriptional regulators and other proteins to induce specific effects on cell survival, proliferation, and differentiation, establishing an additional signaling mode for the cleavable RTKs. On the other hand, the same process can facilitate RTK turnover and proteasomal degradation. In this review we focus on the regulation of RTK shedding and gamma-secretase cleavage, as well as signaling promoted by the soluble RTK ICDs. In addition, therapeutic implications of increased knowledge on RTK cleavage on cancer drug development are discussed.

Fig. 1

Regulated intramembrane proteolysis of RTKs. a RTK ectodomains are shed by cleavage at the extracellular juxtamembrane domains by sheddases, such as ADAM17 or ADAM10. Ligand activation of RTK may result in exposure of phosphatidylserines on the cell surface resulting in a conformational change in ADAM17 facilitating access to the RTK cleavage site. b After shedding of the ectodomain, gamma-secretase complex, consisting of APH-1, nicastrin, PEN-2, and presenilin, gains access to membrane-bound RTK fragment. Nicastrin can now interact with the short RTK ectodomain. RTK binding to the gamma-secretase complex induces further conformational changes in the gamma-secretase subunits that result in substrate translocation to the active site. Cleavage of the RTK substrate in transmembrane domain results in the release of the soluble ICD into the cell cytoplasm. RTK receptor tyrosine kinase, APH-1 anterior pharynx defective-1, PEN-2 presenilin enchancer-2, ICD intracellular domain fragment

Fig. 2

Functional significance of RTK fragments generated by RIP. The reported functions associated with nuclear localization of ICDs include roles in neural development, mammary gland development, and lung development as well as with breast cancer. Mitochondrial localization has been associated with regulation of apoptosis. Cytoplasmic ICD localization allows activation of other receptors, such as NMDA. Downregulation of RTK signaling has also been associated with rapid localization of ICDs to proteasome after gamma-secretase cleavage. The release of shed ectodomains may also contribute to downregulation of RTK signaling by sequestering ligands. RTK receptor tyrosine kinase, RIP regulated intramembrane proteolysis, ICD intracellular domain fragment, NMDA N-methyl-d-aspartate